Sulfamide-metalloprotease inhibitors

ABSTRACT

This invention relates to sulfamides of formula (I) that are inhibitors of metalloproteases, pharmaceutical compositions containing them, methods for their use and methods for preparing these compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional of application Ser. No. 09/009,951, filed Jan. 21, 1998, now U.S. Pat. No. 5,998,412 and this application also claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Application No. 60/036,714, filed Jan. 23, 1997 and U.S. Provisional Application No. 60/062,209, filed Oct. 16, 1997. The entire disclosures of these prior applications are considered as being part of the disclosure of this divisional application and are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to compounds that inhibit metalloproteases such as matrix metalloproteases, particularly interstitial collagenases, as well as TNF α-convertase and related sheddases and are therefore useful in the treatment of mammals having disease states alleviated by the inhibition of such metalloproteases.

2. Background Information and Related Disclosures

Matrix metalloproteases ("MMPs") are a family of proteases (enzymes) involved in the degradation and remodeling of connective tissues. Members of this family of endopeptidase enzymes are present in various cell types that reside in or are associated with connective tissue, such as fibroblasts, monocytes, macrophages, endothelial cells, and invasive or metastatic tumor cells. MMP expression is stimulated by growth factors and cytokines in the local tissue environment, where these enzymes act to specifically degrade protein components of the extracellular matrix, such as collagen, proteoglycans (protein core), fibronectin and laminin. These ubiquitous extracellular matrix components are present in the linings of joints, interstitial connective tissues, basement membranes, and cartilage. Excessive degradation of extracellular matrix by MMPs is implicated in the pathogenesis of many diseases, including rheumatoid arthritis, osteoarthritis, multiple sclerosis, bone resorptive diseases (such as osteoporosis), chronic obstructive pulmonary disease, restenosis, cerebral hemorrhaging associated with stroke, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal and gastric ulceration, ulceration of skin, aneurysmal disease, and in complications of diabetes. MMP inhibition is, therefore, recognized as a good target for therapeutic intervention.

The MMPs share a number of properties, including zinc and calcium dependence, secretion as zymogens, and 40-50% amino acid sequence homology. The MMP family currently consists of at least fifteen enzymes, and includes collagenases, stromelysins, gelatinases, matrilysin, metalloelastase, and membrane-type MMP, as discussed in greater detail below.

Interstitial collagenases catalyze the initial and rate-limiting cleavage of native collagen types I, II, and III. Collagen, the major structural protein of mammals, is an essential component of the matrix of many tissues, for example, cartilage, bone, tendon and skin. Interstitial collagenases are very specific matrix metalloproteases which cleave these collagens to give two fragments which spontaneously denature at physiological temperatures and therefore become susceptible to cleavage by less specific enzymes. Cleavage by the collagenases results in the loss of structural integrity of the target tissue, essentially an irreversible process. There are currently three known human collagenases. The first is human fibroblast-type collagenase (HFC, MMP-1, or collagenase-1) that is produced by a wide variety of cells including fibroblasts and macrophages. The second is human neutrophil-type collagenase (HNC, MMP-8, or collagenase-2) which has so far only been demonstrated to be produced by neutrophils. The most recently discovered member of this group of MMPs is human collagenase-3 (MMP-13) which was originally found in breast carcinomas, but has since shown to be produced by chondrocytes. The only collagenase known to exist in rodents is the homolog of human collagenase-3.

The gelatinases include two distinct, but highly related, enzymes: a 72-kD enzyme (gelatinase A, HFG, MMP-2) secreted by fibroblasts and a wide variety of other cell types, and a 92-kD enzyme (gelatinase B, HNG, MMP-9) released by mononuclear phagocytes, neutrophils, corneal epithelial cells, tumor cells, cytotrophoblasts and keratinocytes. These gelatinases have been shown to degrade gelatins (denatured collagens), collagen types IV (basement membrane) and V, fibronectin and insoluble elastin.

Stromelysins 1 and 2 have been shown to cleave a broad range of matrix substrates, including laminin, fibronectin, proteoglycans, and collagen types IV and IX in their non-helical domains.

Matrilysin (MMP-7, PUMP-1) has been shown to degrade a wide range of matrix substrates including proteoglycans, gelatins, fibronectin, elastin, and laminin. Its expression has been documented in mononuclear phagocytes, rat uterine explants and sporadically in tumors. Other less characterized MMPs include macrophage metalloelastase (MME, MMP-12), membrane type MMP (MMP-14), and stromelysin-3 (MMP-11).

Inhibitors of MMPs provide useful treatments for diseases associated with the excessive degradation of extracellular matrix, such as arthritic diseases (rheumatoid arthritis and osteoarthritis), multiple sclerosis, bone resorptive diseases (such as osteoporosis), the enhanced collagen destruction associated with diabetes, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, corneal or gastric ulceration, ulceration of the skin, tumor invasion and metastasis, aneurysmal disease such as abdominal aortic aneurysm disease, and aberrant angiogenesis. The involvement of individual collagenases in the degradation of tissue collagens probably depends markedly on the tissue. The tissue distribution of human collagenases suggests that collagenase-3 is the major participant in the degradation of the collagen matrix of cartilage, while collagenase-1 is more likely to be involved in tissue remodeling of skin and other soft tissues. Thus, inhibitors selective for collagenase-3 over collagenase-1 are preferred for treatment of diseases associated with cartilage erosion, such as arthritis, etc.

Some inhibitors of MMP also are known to substantially inhibit the release of tumor necrosis factor (TNF) from cells and therefore may be used in the treatment of conditions mediated by TNF. Such uses include, but are not limited to, the treatment of inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, cachexia and anorexia, acute infections, shock states, restenosis, graft versus host reactions and autoimmune disease. Compounds of this invention may inhibit TNF release without inhibiting the MMPs.

In addition to these effects on the release of TNF from cells, MMP inhibitors and related compounds have also been shown to inhibit the release of other biologically active molecules from cells, including soluble receptors (CD30 and receptors for TNF (p55 and p75), IL-6, IL-1 and TSH), adhesion molecules (e.g., L-selectin, ICAM-1, fibronectin) and other growth factors and cytokines, including Fas ligand, TGF-α, EGF, HB-EGF, SCF and M-CSF. The release of such molecules is facilitated by several proteolytic proteins known as sheddases. Inhibition of the release or shedding of such molecules by inhibiting the sheddases may be of benefit in a number of disease states, including rheumatoid arthritis, multiple sclerosis, vascular disease, Type II diabetes, HIV, cachexia, psoriasis, allergy, hepatitis, inflammatory bowel disease, and cancer. Since non-specific inhibition of the shedding enzymes (sheddases) may have opposite pharmacological effects, selectivity will be a particular advantage, e.g., the inhibition of TNF release without the concurrent inhibition of TNF receptor release.

The design and uses of MMP inhibitors is described, for example, in J. Enzyme Inhibition, 2, 1-22 (1987); Drug News & Prospectives, 3(8), 453-458 (1990); Arthritis and Rheumatism, 36(2), 181-189 (1993); Arthritis and Rheumatism, 34(9), 1073-1075 (1991Seminars in Arthritis and Rheumatism, 19(4), Supplement 1 (February), 16-20 (1990); Drugs of the Future, 15(5), 495-508 (1990); Annals N.Y. Acad. Sci., 157, (1996), and J. Enzyme Inhibition, 2, 1-22 (1987). MMP inhibitors are also the subject of various patents and patent applications, for example, U.S. Pat. Nos. 5,189,178 and 5,183,900, European Published Patent Applications 438 223, 606 426, and 276 436, and Patent Cooperation Treaty International Applications 92/21360, 92/06966, 92/09563, and 94/25434.

SUMMARY OF THE INVENTION

In a first aspect, this invention provides hydroxamic acids and their derivatives selected from the group of compounds represented by formula (I): ##STR2## wherein: R¹ and R² are independently selected from hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclo, heterocycloalkyl, heteroalkyl, or -(alkylene)-C(O)-X where X is alkyl, haloalkyl, alkoxy, haloalkyloxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, heteroaryloxy, hydroxy, aralkyloxy, heteroaralkyloxy, or heteroaryl; or R¹ and R² together with the carbon atom to which they are attached form a carbocycle or a heterocycle;

R³ is hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, heteroalkyl, (diphenylmethyl)alkyl, or -(alkylene)-C(O)-X where X is alkyl, haloalkyl, alkoxy, haloalkyloxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, heteroaryloxy, hydroxy, aralkyloxy, heteroaralkyloxy, or heteroaryl; or R³ together with either R¹ or R² and the atoms to which they are attached forms a heterocycloamino group;

R¹⁰ is --NR¹¹ OR¹² wherein:

R¹¹ and R¹² are independently selected from hydrogen, alkyl, or aralkyl;

R²⁰ and R²¹ are independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaralkyl, or heteroaralkenyl; or R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a heterocycloamino group or an optionally substituted tetrahydropyridine or hexahydroazepine ring; or either of R²⁰ or R²¹ together with R³ forms an alkylene group; and their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers, provided that R²⁰ and R²¹ together with the nitrogen atom to which they are attached do not form a morpholino ring either:

(i) when R¹ and R³ are hydrogen and R² is aralkyl; or

(ii) when R¹ and R³ together with the atoms to which they are attached form a tetrahydroisoquinoline ring and R² is hydrogen.

In a second aspect, this invention provides carboxylic acids selected from the group of compounds represented by formula (I): ##STR3## wherein: R¹ and R² are independently selected from hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclo, heterocycloalkyl, heteroalkyl, or -(alkylene)-C(O)-X where X is alkyl, haloalkyl, alkoxy, haloalkyloxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, heteroaryloxy, hydroxy, aralkyloxy, heteroaralkyloxy, or heteroaryl; or R¹ and R² together with the carbon atom to which they are attached form a carbocycle or a heterocycle;

R³ is hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, heteroalkyl, (diphenylmethyl)alkyl, or -(alkylene)-C(O)-X where X is alkyl, haloalkyl, alkoxy, haloalkyloxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, heteroaryloxy, hydroxy, aralkyloxy, heteroaralkyloxy, or heteroaryl; or R³ together with either R¹ or R² and the atoms to which they are attached form a heterocycloamino group;

R¹⁰ is --OH;

R²⁰ is hydrogen or alkyl; and

R²¹ is cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaralkyl or heteroaralkenyl; or

R²⁰ and R²¹ together with the nitrogen atom to which they are attached form either:

(i) a heterocycloamino group substituted with at least one substituent selected from cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl-Q-, aryl-Q-, or heteroaryl-Q- where Q is an alkylene chain in which a methylene group is optionally replaced by --C(O)--, --O--, --S(O)n-- (where n is an integer from 0 to 2), --NR-- (where R is hydrogen or alkyl), --NR^(a) C(O)--, --C(O)NR^(a) (where R^(a) is hydrogen or alkyl), --NR^(b) SO₂ --, or --SO₂ NR^(b) -- (where R^(b) is hydrogen or alkyl);

(ii) a heterocycloamino group that is fused to a cycloalkyl, aryl or heteroaryl ring; or

(iii) an optionally substituted tetrahydropyridine or hexahydroazepine ring;

or either of R²⁰ or R²¹ together with R³ forms an alkylene group; and their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers, provided that:

(i) R¹, R², and R³ are not all hydrogen; and

(ii) when R¹ and R³ are hydrogen and R² is alkyl, then R²¹ is not pyridylalkyl.

In a third aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.

In a fourth aspect, this invention provides a method of treatment of a disease in a mammal treatable by administration of a metalloproteinase inhibitor, comprising administration of a therapeutically effective amount of a compound of formula (I) or its pharmaceutically acceptable salt.

In a fifth aspect, this invention provides processes for preparing compounds of formula (I).

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

"Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like.

"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.

"Alkenyl" means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.

"Alkenylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenylene, 2-propenylene, and the like.

"Acyl" means a radical --C(O)R where R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, or heterocyclo, e.g., acetyl, benzoyl, thenoyl, and the like.

"Acyloxy" means a radical --OC(O)R where R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, or haloalkyl, e.g., acetoxy, 3,3,3-trifluoroacetoxy and the like.

"Acylamino" means a radical --NRC(O)R' where R is hydrogen or alkyl and R' is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkenyl, or heteroaralkyl, e.g., acetylamino, trifluoroacetylamino, benzoylamnino, methylacetylamino, and the like.

"Sulfonylamino" means a radical --NRSO₂ R' where R is hydrogen or alkyl and R' is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, haloalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkenyl, or heteroaralkyl, e.g., methylsulfonylamino, benzylsulfonylamino, N-methylaminosulfonylamino, and the like.

"Halo" means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro.

"Haloalkyl" means alkyl substituted with one or more same or different halo atoms, e.g., --CH₂ Cl, --CF₃, --CH₂ CF₃, --CH₂ CCl₃, and the like.

"Cycloalkyl" means a saturated monovalent cyclic hydrocarbon radical of three to six ring carbons, e.g., cyclopropyl, cyclopentyl, cyclohexyl, and the like.

"Carbocycle" means a saturated, cyclic group of 3 to 8 ring atoms in which all the ring atoms are carbon, e.g., cyclopentyl, cyclohexyl, and the like.

"Monosubstituted amino" means a radical --NHR where R is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or an amino protecting group, e.g., methylamino, (1-methylethyl)amino, phenylamino, and the like.

"Disubstituted amino" means a radical --NRR' where R and R' are independently alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or an amino protecting group. Representative examples include, but are not limited to dimethylamino, methylethylamino, di(1-methylethyl)amino, methylbenzylamino, and the like.

"Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms and optionally substituted independently with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, halo, nitro, acyloxy, cyano, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, heteroaryl, heteroaralkyl, --OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl, optionally substituted phenylalkyl, or heteroaralkyl), --NRR' (where R and R' are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, heteroaryl, or heteroaralkyl), --C(O)R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl), --S(O)_(n) R (where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl, optionally substituted phenylalkyl, or heteroaralkyl), --SO₂ NRR' (where R and R' are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, heteroaryl or heteroaralkyl), --COOH, -(alkylene)-COOH, -(alkenylene)-COOH, --COOR^(a), -(alkenylene)-COOR^(a), -(alkylene)-COOR^(a) (where R^(a) is alkyl, optionally substituted phenylalkyl, or heteroaralkyl), --CONR'R", -(alkylene)-CONR'R", (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, heteroaryl, and heteroaralkyl), --NRC(O)R' (where R is hydrogen or alkyl and R' is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, heteroaryl, heteroaralkenyl, or heteroaralkyl), --NRSO₂ R' (where R is hydrogen or alkyl and R' is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted phenylalkenyl, heteroaryl, heteroaralkenyl, or heteroaralkyl), or --NRSO₂ NR'R" (where R is hydrogen or alkyl and R' and R" are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl). More specifically the term aryl includes, but is not limited to, phenyl, 1-napthyl and 2-naphthyl, and the derivatives thereof.

"Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. The heteroaryl ring is optionally substituted independently with one or more substituents, preferably one or two substituents, selected from alkyl, haloalkyl, halo, nitro, cyano, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, --OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl or optionally substituted phenylalkyl), --NRR' (where R and R' are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl), --C(O)R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl), --S(O)_(n) R (where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, or optionally substituted phenylalkyl), --SO₂ NRR' (where R and R' are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl)], --COOH, -(alkylene)-COOH, -(alkenylene)COOH, --COOR^(a), -(alkenylene)-COOR^(a), -(alkylene)-COOR^(a) (where R^(a) is alkyl, or optionally substituted phenylalkyl), --CONR'R", -(alkylene)-CONR'R", (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, or optionally substituted phenylalkyl), --NRC(O)R' (where R is hydrogen or alkyl and R' is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl), --NRSO₂ R' (where R is hydrogen or alkyl and R' is alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl), --NRSO₂ NR'R" (where R is hydrogen or alkyl and R' and R" are independently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted phenylalkenyl), or an amino protecting group. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzisoxazolyl, benzothiophenyl and benzodiazepin-2-one-5-yl, and the derivatives thereof. "Optionally substituted phenyl" means phenyl ring which is optionally substituted with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, halo, nitro, cyano, --NRR' (where R and R' are independently selected from hydrogen or alkyl), --OR (where R is hydrogen, alkyl or haloalkyl), --COOR^(a) (where R^(a) is hydrogen or alkyl) or --CONR'R" (where R' and R" are independently selected from hydrogen or alkyl). Representative examples include, but are not limited to, phenyl, 3-chlorophenyl, 4-(methylthio)phenyl, and the like.

"Heterocycloamino" means a saturated monovalent cyclic group of 4 to 8 ring atoms, wherein at least one ring atom is N and optionally contains one or two additional ring heteroatoms selected from the group consisting of N, O, or S(O)_(n) (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocycloamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally substituted with one or more substituents, preferably one or two substituents, selected from alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, diphenylmethyl, (diphenylmethyl)alkyl, halo, cyano, acyl, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, --OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), --S(O)_(n) R [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, heterocyclo, aryl, heteroaryl, aralkyl, or heteroaralkyl], --P(O)(NR^(b) R^(c))₂ (where R^(b) and R^(c) are independently selected from alkyl or aralkyl), --COOH, -(alkylene)-COOH, -(alkenylene)-COOH, --COOR^(a), -(alkylene)-COOR^(a), -(alkenylene)COOR^(a) (where R^(a) is alkyl, heteroalkyl, aralkyl, or heteroaralkyl), --CONR'R", -(alkylene)CONR'R", (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), --COCH(R')NH₂ (where R' is a side chain of a natural or unnatural alpha amino acid in which any functional group present may be protected), an amino protecting group, or 1,3-dihydro-2H-1,4-benzodiazepin-2-one wherein the N-1 and C-3 positions may be optionally substituted, independently of each other, with a substituent selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, acyl, and heteroaralkyl. More specifically the term heterocycloamino includes, but is not limited to, pyrrolidino, piperidino, morpholino, piperazino, indolino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 1,2,3,4-tetrahydro-α, -β, or -γ, -carbolino, tetrahydroisoquinolyl, and 1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, and the derivatives thereof.

"Optionally substituted tetrahydropyridine or hexahydroazepine ring" means a tetrahydropyridine or a hexahydroazepine ring that is optionally substituted with one or two substituents selected from alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, diphenylmethyl, (diphenylmethyl)alkyl, acyl, hydroxy, --COOH, -(alkylene)-COOH, -(alkenylene)-COOH, --COOR^(a), -(alkylene)-COOR^(a), -(alkenylene)-COOR^(a) (where R^(a) is alkyl, heteroalkyl, aralkyl, or heteroaralkyl), --S(O)_(n) R [where n is an integer from 1 to 2 and R is hydrogen (provided that n is 0), alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, heteroaryl, aralkyl, or heteroaralkyl], --CONR'R", and -(alkylene)-CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl). Representative examples include, but are not limited to, 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine, and the like.

"Heterocycle" or "Heterocyclo" means a saturated cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)_(n) (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocyclo ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acylamino, amino, monosubstituted amino, disubstituted amino, --OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), --C(O)R (where R is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, haloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, or heteroaralkenyl), --S(O)_(n) R [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, heteroaryl, aralkyl, or heteroaralkyl], --COOH, -(alkylene)-COOH, --COOR^(a), -(alkylene)-COOR^(a) (where R^(a) is alkyl, heteroalkyl, aralkyl, or heteroaralkyl), --CONR'R", -(alkylene)-CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl) or an amino protecting group. More specifically the term heterocyclo includes, but is not limited to, tetrahydropyranyl, piperidino, piperazino, morpholino and thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, and the derivatives thereof.

"Heteroalkyl" means an alkyl, cycloalkyl, or cycloalkylalkyl radical as defined above, carrying a substituent selected from --NR^(a) R^(b), --OR^(c), --S(O)_(n) R^(d), --P(O)(OR^(e))(OR^(f)), --P(O)(OR^(e))R^(g), or --P(O)(NR^(h) R^(i))₂, wherein n is an integer from 0 to 2, R^(a) is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, or acyl; R^(b) is hydrogen, alkyl, aryl, aralkyl, acyl, --SO₂ R (where R is alkyl, haloalkyl, amino, monosubstituted amino or disubstituted amino), --COOR (where R is hydrogen, alkyl, aralkyl, or heteroaralkyl), --CONR'R", -(alkylene)CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), --P(O)(OR)₂ (where each R is independently alkyl, aryl or aralkyl), --P(O)(NR'R")₂ (where R' and R" are independently selected from alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or --P(O)(OR)R' (where R is alkyl, aryl, or aralkyl and R' is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R^(c) is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, acyl, --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), --P(O)(OR)₂ (where each R is independently alkyl, aryl or aralkyl), --P(O)(NR'R")₂ (where R' and R" are independently selected from alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl), or --P(O)(OR)R' (where R is alkyl, aryl, or aralkyl and R' is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); R^(d) is hydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, amino, monosubstituted amino, or disubstituted amino; R^(e) and R^(f) are independently selected from alkyl or aryl; R_(g) is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R_(h) and R^(i) are independently selected from alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. Representative examples include, but are not limited to 2-methoxyethyl, benzyloxymethyl, thiophen-2-ylthiomethyl, and the like;

"Cycloalkylalkyl" means a radical --R^(a) R^(b) where R^(a) is an alkylene group and R^(b) is a cycloalkyl group as defined above e.g., cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like.

"Aralkyl" means a radical --R^(a) R^(b) where R^(a) is an alkylene group and R^(b) is an aryl group as defined above e.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.

"Aralkenyl" means a radical --R^(a) R^(b) where R^(a) is an alkenyl group and R^(b) is an aryl group as defined above e.g., 3-phenyl-2-propenyl, and the like.

"Heteroaralkyl" means a radical --R^(a) R where R^(a) is an alkylene group and R^(b) is a heteroaryl group as defined above e.g., pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.

"Heteroaralkenyl" means a radical --R^(a) R^(b) where R^(a) is an alkenyl group and R^(b) is a heteroaryl group as defined above e.g., 3-pyridin-3-ylpropen-2-yl, and the like.

"Heterocycloalkyl" means a radical --R^(a) R^(b) where R^(a) is an alkylene group and R^(b) is a heterocyclo group as defined above e.g., tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl, and the like.

"Alkoxy", "aryloxy", "heteroaryloxy", "aralkyloxy", or "heteroaralkyloxy" means a radical --OR where R is an alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl respectively, as defined above e.g., methoxy, phenoxy, pyridin-2-yloxy, benzyloxy, and the like.

"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "heterocyclo group optionally mono- or di-substituted with an alkyl group" means that the alkyl may but need not be present, and the description includes situations where the heterocyclo group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.

"Amino protecting group" refers to those organic groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures e.g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoroacetyl, 2-trimethylsilylethanesulfonyl (SES), and the like.

Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers".

Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".

The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. For example, if the R¹ and R² substituents in a compound of formula (I) are different, then the carbon to which they are attached is an asymmetric center and therefore the compound of formula (I) can exist as an (R)- or (S)-stereoisomer. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992).

A "pharmaceutically acceptable excipient" means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable excipient" as used in the specification and claims includes both one and more than one such excipient.

A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:

(1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or

(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

"Pro-drugs" means any compound which releases an active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound of formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of formula (I), and the like.

"Treating" or "treatment" of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,

(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or

(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

A "therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

Nomenclature

The naming and numbering of the compounds of this invention is illustrated below. ##STR4##

The nomenclature used in this application is generally based on the IUPAC recommendations, e.g., a compound of formula (I):

where R¹⁰ is --NHOH, R¹ is 2-propyl, R² is hydrogen, R³ is benzyl, the stereochemistry at the carbon to which R¹ and R² are attached is (RS), and R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a piperidino ring substituted at the 4-position with phenoxy, is named N-hydroxy-2-(RS)-{[benzyl-4-(phenoxy)piperidine-1 -sulfonyl]amino}-3-methylbutyramide;

where R¹⁰ is --OH, R' is Me, R² and R³ are hydrogen, the stereochemistry at the carbon to which R' and R² are attached is (RS), and R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a piperazino ring substituted at the 4-position with 4-chlorophenyl, is named 2-(RS)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}propionic acid;

where R¹⁰ is --NHOH, R¹ and R² form a cyclopentane ring, R³ is hydrogen, the stereochemistry at the carbon to which R¹ and R² are attached is (RS), and R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a piperazino ring substituted at the 4-position with 4-chlorophenyl, is named N-hydroxy-1-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}cyclopentane-1-(RS)-carboxamide;

where R¹⁰ is --NHOH, R¹ and R³ form a piperidine ring, R² is hydrogen, the stereochemistry at the carbon to which R¹ and R² are attached is (R), and R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a piperazino ring substituted at the 4-position with phenoxy, is named N-hydroxy-1-[4-(phenoxy)piperazine-1-sulfonyl]piperidine-2-(R)-carboxamide, and

where R¹⁰ is --NHOH, R² is hydrogen, R¹ and R³ together with the nitrogen atom to which they are attached form a piperazino ring substituted at the 4-position with N,N-dimethylaminocarbonyl and R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a 1,2,3,6-tetrahydropyridine substituted at the 4-position with 4-fluorophenyl, is named N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxamide.

Representative compounds of this invention are as follows:

I. Compounds of formula (I) where R² =hydrogen, R¹⁰ =--NR¹¹ OR¹² where R¹¹ and R¹² are hydrogen, and other groups are as defined below are:

    __________________________________________________________________________     CPD                                                                               Stereo-                                                                       #  chem R.sup.1 R.sup.3 --NR.sup.20 R.sup.21 = heterocycloamino group                                                            M. Pt.° C.                                                              Mass Spec.                 __________________________________________________________________________     1  2(R)                                                                               2-propyl benzyl    piperidino        80.6-85.7                                                                              370 M + H                    2  H benzyl morpholino  329 M+                                                 3  H benzyl 4-methoxypiperidino  357 M+                                        4  H benzyl 4-(4-chlorophenyl)piperazino 75.6-76.9 439 M + H                   5  H benzyl 4-chloropiperidino  362 M + H                                      6  H benzyl 4-phenoxypiperidino  420 M + H                                     7  H pyridin-3-ylmethyl 4-(4-chlorophenyl)piperazino.TFA salt 159.2-159.                                                         5 440 M + H                  8  H H 4-(4-chlorophenyl)piperazino 151.3-152.1 348 M+                         9  H benzyl 4-(4-trifluoromethylphenyl)piperazino 49.7-51.4 472 M+                                                                10  H benzyl                                                                  4-phenylpiperazino.TFA                                                          salt 45.1-72.9 405 M                                                          + H                          11  H benzyl 4-(4-methoxyphenyl)piperazino.TFA 46.4-67.5 435 M + H                                                                    salt                    12  H benzyl 4-(4-fluorophenyl)piperazino.TFA salt 126.7-127.3 422 M+                                                             13  H benzyl                                                                  4-(pyridin-yl)piperazi                                                         no 87.5-122.5 405 M+                                                            14 2(R) methyl                                                                benzyl 4-(4-chlorophen                                                         yl)piperazino                                                                  76.7-79.8 453 M + H                                                             15  H methyl                                                                  4-(4-chlorophenyl)pipe                                                         razino.TFA salt                                                                141.2-143.2 363 M + H        16  H 2-methoxyethyl 4-(4-chlorophenyl)piperazino.TFA salt 54.1-57.7                                                             406 M+                       17  H benzyl 4-(4-methylphenyl)piperazino.TFA salt 130.2-131.1 419 M +                                                           H                            18  H benzyl 4-cyclopentylpiperazino.TFA salt 156.2-156.8 397 M + H                                                               19  H benzyl                                                                  4-(4-chlorophenoxy)pip                                                         eridino 39-47.7 454 M                                                          + H                          20 2(R) methyl H 4-(4-chlorophenyl)piperazino 143 362 M+                       21 2(R) methyl H 4-(4-chlorophenyl)piperazino.TFA salt 99-101 363 M + H        22 2(S) methyl H 4-(4-chlorophenyl)piperazino  363.1 M + H                     23 2(RS) methyl H 4-(4-chlorophenyl)piperazino 75 efferves. 363.2 M + H        24  H pyridin-3-ylmethyl 4-phenoxypiperidino.TFA salt 127.5-128.9 421 M                                                          + H                          25  H H 4-(4-fluorophenyl)piperazino.TFA salt 51-54 333 M + H                  26  H H 4-phenylpiperazino.TFA salt 123.1-126.1 315 M + H                      27  H H 4-(4-methoxyphenyl)piperazino.TFA 119.4-120.9 343 M - H                                                                       salt                    28  H H 4-(4-methylphenyl)piperazino.TFA salt 62-76 329 M + H                  29  H H 4-(4-trifluoromethylphenyl)piperazino 144-145 383 M + H                                                                   30  H H 4-phenoxypipe                                                         ridino 110-114 330 M                                                           + H                          31  H H 4-(4-ethoxyphenyl)piperazino.TFA salt 56-61.5 359 M + H                                                                   32  H H 4-(2-chloroph                                                         enyl)piperazino                                                                165-165.5 347 M - H                                                             33  H H 4-(3-chloroph                                                         enyl)piperazino                                                                138.1-138.6 348 M+                                                              34  H H 4-(4-nitrophe                                                         nyl)piperazino  358 M                                                          - H                          35  H H 4-(4-benzyloxyphenyl)piperazino 162 efferves. 419 M - H                                                                   36  H H 4-(4-phenoxyp                                                         henyl)piperazino 131                                                           efferves. 407 M + H                                                             37  H H 4-(4-cyanophe                                                         nyl)piperazino                                                                 155-155.5 340 M + H                                                             38  H H 4-(4-biphenyl                                                         )piperazino  391.2 M                                                           + H                          39  H H 4-(3-methoxyphenyl)piperazino 134.1-134.9 345 M + H                    40  H H 4-(3-trifluoromethylphenyl)piperazino 110.9 efferves. 382 M+                                                              41 2(RS) ethyl H                                                              4-(4-chlorophenyl)pipe                                                         razino  376 M+                                                                  42  H H 4-(pyridin-2-                                                         yl)piperazino 75.1                                                             efferves. 316 M + H                                                             43  H H 4-[4-(1,1,2,2                                                         -tetrafluoroethoxyphen                                                         yl)- 115-117.1 429 M                                                           - H                              piperazino                                                                 44 2(RS) n-butyl H 4-(4-chlorophenyl)piperazino 156-156.4 404 M+                                                                  45  H H 4-(3-phenoxyp                                                         henyl)piperazino                                                               126.5 efferves. 405 M                                                          - H                          46  H H 4-(3-benzyloxyphenyl)piperazino 129-130 421 M + H                      47  H H 4-(pyrimidin-2-yl)piperazino 144-145 316 M+                            48 2(R) methyl H 4-(5-chloropyridin-2-yl)piperazino 102 efferves. 363                                                            M+                           49 2(R) methyl H 4-phenoxypiperidino 55-62 344.1 M + H                         50 2(R) 2-propyl H 4-(5-chloropyridin-2-yl)piperazino 146.7-147 392.1 M                                                          + H                          51 2(R) 2-propyl H 4-(4-chlorophenyl)piperazino 154.1-154.8 391.1 M + H        52 2(R) tert-butyl H 4-(4-chlorophenyl)piperazino 185-186 405.1 M + H                                                             53  H H 4-(pyridin-3-                                                         yl)piperazino                                                                  179.3-179.6 316 M + H        54  H H 4-(5-trifluoromethylpyridin-2-yl)- 145.2-145.5 384 M + H                                                                      piperazino                                                                 55 2(R) methyl H                                                              4-(4-benzyloxy)piperid                                                         ino 68-71 358.1 M + H        56 2(R) methyl H 4-(3-phenylpropyloxy)piperidino 89-93.5 386.1 M + H                                                              57 2(R) methyl H                                                              4-(4-chlorophenoxy)pip                                                         eridino 93-94 378.1 M                                                          + H                          58 2(R) methyl H 4-(5-trifluoromethylpyridin-2-yl)- 121.3-121.7 398 M +                                                          H                                piperazino                                                                 59 2(R) 2-propyl H 4-(4-chlorophenoxy)piperidino 139.2-139.6 406.1 M +                                                           H                            60 2(R) 2-propyl H 4-(5-trifluoromethylpyridin-2-yl)- 158.3-158.8 426.1                                                          M + H                            piperazino                                                                 61 2(R) tert-butyl H 4-(5-chloropyridin-2-yl)piperazino 218.4-218.6 405                                                          M + H                        62 2(R) (1-methyl-1- H 4-(4-chlorophenyl)piperazino 158.5-159.6                                                                     methylthio)ethyl                                                             63  H 3-phenylpropyl                                                          4-(pyridin-2-yl)pipera                                                         zino 58-59.5 434.1 M                                                           + H                          64  H 3-phenylpropyl 4-(pyridin-3-yl)piperazino 64-65 434.1 M + H                                                                 65 2(R) methyl H                                                              4-(benzylaminocarbonyl                                                         )piperidino 85.9-87.9                                                          385.1 M + H                  66 2(R) methyl H 4-[(4-chlorobenzylaminocarbonyl) 86.6-88.3 433.2 M + H            methyl]piperidino                                                          67 2(R) methyl H 4-(4-chlorobenzoyl)piperidino 77.4-79.7 390 M + H                                                                68 2(R) methyl H                                                              4-(4-chlorobenzylcarbo                                                         nyl)piperazino                                                                 81.5-82.4 405.1 M + H        69 2(R) methyl H 4-(4-chlorobenzoyl)piperazino 107.9 decomp. 391.1 M +                                                           H                            70  H H 4-(phenylamino)piperidino.TFA salt 55.8-57.2 329 M + H                 71 2(R) methyl H 4-(benzyl)piperidino 73 efferves. 342.2 M + H                 73 2(R) methyl H 4-(3-chlorophenoxy)piperidino 90 efferves. 378.1 M + H        74 2(R) 2-propyl H 4-(4-benzyloxyphenyl)piperazino 149-156 463 M + H                                                              75 2(R) 2-propyl H                                                            4-(4-biphenyl)piperazi                                                         no 150.5 efferves.                                                             433.2 M + H                  76 2(R) (1-methyl-1- H 4-(4-chlorophenoxy)piperidino 116.5-117.2                                                                    methylthio)ethyl                                                             77 2(R) methyl H                                                              4-(4-chlorophenylthio)                                                         piperidino 114                                                                 efferves. 392 M - H                                                             78 2(R) 2-propyl                                                              pyridin-3-ylmethyl                                                             4-(phenoxy)piperidino                                                          128.9 efferves. 463.1                                                          M + H                        79 2(R) 2-propyl H 4-(phenoxy)piperidino 65.8 efferves. 372.2 M + H                                                               80 2(R) H 2-phenoxyet                                                         hyl 4-(pyridin-4-yl)pi                                                         perazino  436.1 M + H        81 2(RS) benzyloxymethyl H 4-(5-chloropyridin-2-yl)piperazino 82-89.7                                                            470.1 M + H                  82 2(RS) phenylethyl methyl 4-(5-chloropyridin-2-yl)piperazino 145.9-146                                                         .8 468.1 M + H                                                                  83 2(R) 2-propyl                                                              pyridin-3-ylmethyl                                                             4-(5-bromopyridin-2-yl                                                         )piperazino  527.1 M                                                           + H                          84 2(R) 2-propyl H (4-benzyl-4-hydroxy)piperidino 136.1-139 386 M + H                                                             85 2(R) benzyl H                                                              4-(4-chlorophenyl)pipe                                                         razino 167-168 439 M                                                           + H                          86 2(R) 2-propyl H 4-[4-(pyridin-3-ylmethyloxy)phenyl]- 177.5-177.8                                                              464.1 M + H                      piperazino                                                                 87 2(R) methyl H 4-[1-(phenyl)hydroxymethyl]piperidino 91.9-94.4 358 M                                                           + H                          88  H H 4-(4-nitrophenylamino)piperidino  374 M + H                            89  H 2-phenoxyethyl 4-(pyridin-2-yl)piperazino 134-134.6 436.1 M + H                                                             90 2(RS) benzyloxymet                                                         hyl methyl 4-(5-chloro                                                         pyridin-2-yl)piperazin                                                         o  484.1 M + H                                                                  91 2(RS) 2-phenylethy                                                         l H 4-(5-chloropyridin                                                         -2-yl)piperazino                                                               125.5-128.1 454 M + H        92 2(R) 2-propyl H 4-(2-methylpyridin-5-yloxy)piperidino 95 efferves.                                                            386 M+                       93 2(R) phenylthiomethyl H 4-(4-chlorobenzoyl)piperidino  498 M + H                                                               94 2(R) methyl ethyl                                                          4-(4-chlorobenzoyl)pip                                                         eridino  418 M + H                                                              95  H H 4-phenylpiper                                                         idino 147.3-147.6 314                                                          M + H                        96 2(R) 2-propyl H 4-{4-[(pyridin-4-ylmethyloxy)phenyl]}- 171.8-172.1                                                            464.1 M + H                      piperazino                                                                 97 2(R) methyl H 4-benzoylpiperidino 94.2-102.9 356 M + H                      98 2(R) 2-propyl H 4-benzoylpiperidino 187.2-187.6 383 M+                      99 2(R) methyl pyridin-3-ylmethyl 4-(4-chlorobenzoyl)piperidino  481 M                                                           + H                          100 2(R) 2-propyl H 4-(5-chloropyridin-2-yloxy)piperidino 97-98.4 407 M                                                          + H                          101 2(R) phenylthiomethyl H 4-(4-bromophenoxy)piperidino  530 M + H                                                               102 2(R) benzylthiome                                                         thyl H 4-(5-chloropyri                                                         din-2-yl)piperazino                                                            86-86.7 486.1 M + H                                                             103 2(R) 4-hydroxyben                                                         zyl H 4-(5-chloropyrid                                                         in-2-yl)piperazino                                                             142 456.1 M + H                                                                 104 2(R) 2-propyl                                                             pyridin-3-ylmethyl                                                             4-(4-bromophenoxy)pipe                                                         ridino 143-146 541 M                                                           + H                          105 2(R) 2-propyl 3-(pyridin-3-yl)propyl 4-(4-bromophenoxy)piperidino                                                            569 M + H                    106 2(R) phenylthiomethyl H 4-(5-chloropyridin-2-yl)piperazino  472 M +                                                          H                            107 2(R) methyl H 4-(4-fluorobenzoyl)piperidino 148.1-148.4 374 M + H                                                             108 2(RS) 2-propenyl                                                          H 4-(5-chloropyridin-2                                                         -yl)piperazino 59.8                                                            390.1 M + H                  109 2(R) 2-propyl H 4-(4-bromophenoxy)piperidino  450.06                             M + H                                                                    110 2(R) phenylthiomethyl methyl 4-(4-chlorobenzoyl)piperidino  512.1 M                                                          + H                          111 2(R) 2-propyl H 4-{4-[(pyridin-2-yl)methyloxy]phenyl}- 124.2-128.5                                                           464 M+                           piperazino                                                                 112 2(R) methyl H 4-(4-methylbenzoyl)piperidino 172.4 efferves. 370 M +                                                          H                            113 2(R) 2-propyl H 4-[4-(pyridin-3-yl)phenoxy]piperidino 108.1-131 449                                                          M + H                        114 2(R) pyridin-2-ylthio- H 4-(5-chloropyridin-2-yl)piperazino 97.8                                                             efferves. 473.08                                                                  methyl    M + H                                                              115 2(R) methyl                                                               3-phenylpropyl                                                                 4-(4-chlorobenzoyl)pip                                                         eridino  508 M + H                                                              116 2(R) methyl H                                                             4-(4-methoxybenzoyl)pi                                                         peridino 184.5 386 M                                                           + H                          117 2(R) thiophen-2-ylthio- H 4-(5-chloropyridin-2-yl)piperazino                                                                 92.5-94.5 478 M + H                                                               methyl                    118 2(R) methyl 2-N,N-dimethylamino- 4-(4-chlorobenzoyl)piperidino  461                                                          M + H                           ethyl                                                                       119 2(R) methyl H 4-(4-chlorophenylsulfonyl)piperazino 180.5-180.9 427                                                           M + H                        120 2(R) 2-propyl H 4-(benzthiazol-2-yl)piperazino 146-148 414.1 M + H                                                            121 2(R) benzylthiome                                                         thyl methyl 4-(4-chlor                                                         obenzoyl)piperidino                                                            526 M + H                    122 2(R) 2-propyl methyl 4-(4-chlorobenzoyl)piperidino 68.9 decomp.                                                               123 2(R) 2-propyl                                                             methyl 4-(benzoxazol-2                                                         -yl)piperidino                                                                 78.5-80 411 M + H                                                               124 2(R) 2-propyl H                                                           4-(benzoxazol-2-yl)pip                                                         erazino 175.2-176.3                                                            398 M + H                    125 2(S) methyl H 4-(4-chlorobenzoyl)piperidino 201.2-201.8                    126 2(R) 2-propyl H 4-[4-(imidazol-1-yl)phenoxy]piperidino 89.2                                                                  efferves. 438.1 M + H        127 2(R) methyl H 4-(4-(chlorophenyl)-4-hydroxy- 75-77.5 378 M + H                                                                    piperidino                                                                 128 2(R) 2-propyl H                                                           4-(quinolin-6-yloxy)pi                                                         peridino 112-142                                                               423.1 M + H                  129 2(R) 2-propyl H 4-phenylpiperidino 154.9-155.1 356.1 M + H                 130 2(R) methyl H 4-(benzoxazol-2-yl)piperidino 136 efferves. 369.1 M +                                                          H                            131 2(R) 2-propyl H 4-(benzimidazol-2-yl)piperidino 143.7 efferves.                                                              396.1 M + H                  132 2(R) methyl H 4-(4-fluorophenylaminocarbonyl)- 104.4-110.4 389.1 M                                                           + H                              piperidino                                                                 133 2(R) 2-propyl H 4-[4-phenylimidazol-2-yl]piperidino 141-142.3 422 M                                                          + H                          134 2(R) 2-propyl H 4-(4-chlorobenzoyl)piperidino 181-182.5 418 M + H                                                             135 2(R) methyl H                                                             4-phenylpiperidino                                                             147.9-148.3 328 M + H        136 2(R) 2-propyl H 4-[5-phenylthiazol-2-yl]piperidino 120-122.1 439 M                                                           + H                          137 2(R) tert-butyl H 4-(5-chloropyridin-2-yloxy)piperidino 235-235.2                                                            405 M + H                    138 2(R) 2-propyl H 4-(benzoxazol-2-yl)piperidino 107-109.5 397.2 M + H        139 2(R) methyl H 4-(2,3,4,5,6-pentamethylbenzoyl)- 128-132 426.2 M + H            piperidino                                                                 140 2(R) benzylthiomethyl H 4-(4-chlorobenzoyl)piperidino  512 M + H                                                              141 2(R) methyl H                                                             4-(5-fluoroindol-3-yl)                                                         piperidino  384 M + H        142 2(R) methyl H 4-(6-fluorobenzisoxazol-3-yl)-  387 M + H                        piperidino                                                                 143 2(R) methyl H 4-(4-chlorobenzoyloxime)piperidino 109.3-131.3 405 M                                                           + H                          144 2(R) methyl H 4-(1-benzimidazol-2-one)piperidino  384 M + H                                                                   145 2(R) methyl H                                                             4-(2,4-difluorobenzoyl                                                         )piperidino  392.1 M                                                           + H                          146 2(R) methyl H 4-(4-chlorophenylsulfonyl)piperidino 158-158.3                                                                  147 2(R) methyl H                                                             4-{[2-(4-chlorophenyl)                                                         -1,3-dioxolan-2-                                                               154.9-155.4 434 M + H            yl]}piperidino                                                             148 2(R) methyl H 4-[4-(phenoxy)benzoyl]piperidino 202-205 448 M + H                                                              149 2(R) methyl H                                                             4-(3-chlorobenzoyl)pip                                                         eridino  390.4 M + H                                                            150 2(R) methyl H                                                             4-(4-fluoro-3-methylbe                                                         nzoyl)piperidino                                                               388.2 M + H                  151 2(R) methyl H 4-(4-trifluoromethylbenzoyl)piperidino  424.2 M + H                                                             152 2(R) methyl H                                                             4-(3-methylbenzoyl)pip                                                         eridino 115-116 370 M                                                          + H                          153 2(RS) 3-phenylpropyl H 4-(5-chloropyridin-2-yl)piperazino 123.3-124                                                          468 M + H                    154 2(R) methyl H 4-(benzimidazol-2-yl)piperazino 108 369 M + H                                                                   155 2(R) methyl H                                                             4-[1-(4-chlorophenyl)h                                                         ydroxymethyl]-                                                                 101.3-103.6 392 M + H            piperidino                                                                 156 2(R) methyl H 4-(thiophen-2-ylcarbonyl)piperidino 107.1-107.9 362 M                                                          + H                          157 2(R) methyl H 4-(benzothiophen-2-ylcarbonyl)- 100.1-111.1 412 M + H            piperidino                                                                 158 2(R) methyl H 4-[(4-chloro-3-trifluoromethylbenzoyl)- 95.5-98 458.1                                                          M + H                            piperidino                                                                 159 2(R) methyl H 4-{[methyl-(4-chlorophenyl)]amino- 79.1-90.2 420.2 M                                                           + H                              carbonyl}piperazino                                                        160 2(R) methyl H 4-(4-tert-butylbenzoyl)piperidino 79-84 412 M + H                                                               161 2(R) methyl H                                                             4-(2-methylbenzoyl)pip                                                         eridino 75-79 370 M +                                                          H                            162 2(R) methyl H 4-(4-phenylbenzoyl)piperidino 100 efferves. 432 M + H        163 2(R) methyl H 4-(benzothiophen-3-yl)piperidino  384 M + H                  164 2(R) methyl H 4-(morpholino-ylcarbonyl)piperidino 88.5-93.5 365 M +                                                          H                            165 2(R) methyl H 4-(6-chloroindol-3-yl)piperidino 95 efferves. 401 M +                                                          H                                 115 liquid                                                                166 2(R) methyl H 4-(5-methylindol-3-yl)piperidino 105 efferves. 381 M                                                           + H                               150 liquid                                                                167 2(R) methyl H 4-(6-methylindol-3-yl)piperidino 115-124 381.1 M + H                                                            168 2(R) methyl H                                                             4-(5-fluoro-1-methylin                                                         dol-3-yl)-  399 M + H            piperidino                                                                 169 2(R) methyl H 4-(4-methylsulfonylbenzoyl)piperidino 88 efferves.                                                             434 M + H                    170 2(R) 2-propyl H 4-(2-phenylbenzoxazol-5-yl)piperazino 165.7-166 474                                                          M + H                        171 2(R) methyl H 4-(4-chloromethylthiobenzoyl)- 95 efferves. 436 M + H            piperidino                                                                 172 2(R) methyl H 4-(4-methylthiobenzoyl)piperidino  402 M + H                 173 2(R) methyl H 4-(benzylcarbonyl)piperidino 61-65 370.1 M + H                                                                  174 2(R) methyl H                                                             4-(pyridin-2-ylcarbony                                                         l)piperidino.HCl 155                                                           efferves. 357 M + H                                                                 salt                    175 2(R) methyl H 4-(pyridin-3-ylcarbonyl)piperidino.HCl 137-147 357.12            salt  M + H                                                                176 2(R) methyl H 4-(indol-3-yl)piperidino 163.3-164.1 367.2 M + H                                                                177 2(R) methyl H                                                             4-(4-chlorophenylamino                                                         carbonyl)-  406.09                                                                  piperazino  M +                                                           H                            178 2(R) tert-butyl H 4-(5-bromopyridin-2-yl)piperazino 144-146.5 452 M                                                          + H                          179 2(R) 2-propyl H 4-(4-fluorophenoxy)piperidino 74.3-75.3 390 M + H                                                             180 2(R) methyl H                                                             3-(4-chlorobenzoyl)pip                                                         eridino 89-93.5 390 M                                                          + H                          181 2(R) methyl H 4-(pyridin-4-ylcarbonyl)piperidino.HCl 153 efferves.                                                           357.12                           salt  M + H                                                                182  H H 4-phenylpiperidino 160-162 378.1 M + H                                183 2(R) 2-propyl H 4-(6-chloropyridin-2-yloxy)piperidino 81-96 407.1 M                                                          + H                          184 2(R) methyl H 4-(naphth-2-yl)piperidino 160-162 378.1 M + H                                                                   185 2(R) 2-propyl H                                                           4-(4-chlorophenyl)pipe                                                         ridino 154.3-154.8                                                             389 M+                       186 2(R) tert-butyl H 4-[5-(thiophen-2-yl)pyridin-2-yl]- 151.5-152.5                                                             454 M + H                        piperazino                                                                 187 2(R) 2-propyl H 4-(6-methylpyridin-2-yloxy)piperidino 147.4-148.9                                                            387 M + H                    188  H H 4-(4-chlorobenzoyl)piperidino  376 M + H                              189 2(R) tert-butyl H 4-(4-chlorobenzoyl)piperidino 171.6-172.1 432 M +                                                          H                            190 2(R) 2-propyl H 4-(4-chlorophenylthio)piperidino 117.9-119.8 421 M+        191 2(R) 2-propyl H 4-(6-chloroindol-3-yl)piperidino 112.1-115.4 429 M                                                           + H                          192  H 3-methylbutyl 4-phenylpiperidino  383 M + H                             193 2(RS) H 2-phenoxyethyl 4-phenylpiperidino  433 M + H                       194 2(RS) H methyl 4-phenylpiperidino  327 M + H                               195 2(RS) H 2-methoxyethyl 4-phenylpiperidino  371 M + H                       196 2(RS) H 2-N,N-dimethyl- 4-phenyipiperidino                                    aminoethyl                                                                  197 2(R) 1-(R)-methylpropyl H 4-(5-chloropyridin-2-yloxy)piperidino                                                              132.3-133.1 421 M + H        198 2(R) 1-(S)-(tert-butoxy)- H 4-(5-chloropyridin-2-yloxy)piperidino                                                            149.6-153.3 465.2 M +                                                          H                              ethyl                                                                        199 2(R) 2-methylpropyl H 4-(5-chloropyridin-2-yloxy)piperidino                                                                  198.2-200 405.1 M + H        200 2(R) 1-(S)-hydroxyethyl H 4-(5-chloropyridin-2-yloxy)piperidino                                                              86.5-89 409 M + H                                                               201 2(R) 1-(S)-methyl                                                         propyl H 4-(5-chloropy                                                         ridin-2-yloxy)piperidi                                                         no 66.2-73.2 421.1 M                                                           + H                          202 2(R) 2,2-dimethylpropyl H 4-(5-chloropyridin-2-yloxy)piperidino                                                              117.2-117.7 435.1 M +                                                          H                            203 2(R) methyl H 4-(benzothiophen-2-yl)piperidino  384 M + H                  204 2(S) methyl H 4-(4-chlorobenzoyl)piperidino 201.2-201.8                    205 2(R) methyl H 4-(quinolin-3-yl-N-oxide)piperidino  395 M + H                                                                  206 2(R) methyl H                                                             4-(4-chlorobenzoyl)-4-                                                         hydroxypiperidino                                                              406 M + H                    207 2(R) cyclohexyl H 4-(5-chloropyridin-2-yloxy)piperidino 171.1-171.4                                                          447 M + H                    208 2(R) 2-propyl H 4-(5-nitropyridin-2-yl)piperazino 92.8 efferves.                                                             403 M + H                    209 2(R) tert-butoxymethyl H 4-(5-chloropyridin-2-yloxy)piperidino                                                               162.5-163 451 M + H                                                             210 2(R) methyl H                                                             4-(4-fluorobenzylamino                                                         carbonyl)- 110-123                                                             404 M + H                        piperazino                                                                 211 2(R) 2-propyl pyridin-3-ylmethyl 4-(5-chloropyridin-2-yloxy)piperidi                                                         no 152.2-152.7 498 M                                                           + H                          212 2(R) 2-propyl pyridin-3-ylmethyl 4-(4-chlorophenoxy)piperidino                                                               140.9-142.1 497 M + H        213 2(R) methyl H 4-[4-(phenoxy)phenylaminocarbonyl]- 119-122 464 M + H            piperazino                                                                 214 2(R) methyl H 4-(4-biphenylaminocarbonyl)piperazino 110-135 448 M +                                                          H                            215 2(R) methyl H 4-[4-(benzyloxy)phenylaminocarbonyl]- 478.1 M + H                                                                   piperazino                                                                 216 2(R) methyl H                                                             4-(naphth-1-yl)piperid                                                         ino 164.2-165 378 M +                                                          H                            217 2(R) 2-methylpropyl H 4-(5-chloropyridin-2-yl)piperazino 83-88                                                               406.2 M + H                  218 2(R) tert-butoxymethyl H 4-(5-chloropyridin-2-yl)piperazino 74-77.5                                                          436.2 M + H                  219 2(R) propyl H 4-(4-chlorophenyl)piperazino 142.4-142.9 391.2 M + H                                                            220 2(R) benzyl H                                                             4-(5-chloropyridin-2-y                                                         loxy)piperidino                                                                76.2-79.5 455.1 M + H        221 2(R) 2-propyl H 4-(4-chlorophenylaminocarbonyl)- 115-128 434.1 M +                                                           H                                piperazino                                                                 222 2(R) 2-propyl pyridin-3-ylmethyl 4-(4-chlorobenzoyl)piperidino                                                               151.6-152.6 509.1 M +                                                          H                            223 2(R) 2-propyl H 4-(4-cyanophenyl)piperazino 76.5-80 efferves. 382 M                                                          + H                          224 2(R) n-propyl H 4-(5-chloropyridin-2-yl)piperazino  392.2 M + H                                                               225 2(RS) phenyl H                                                            4-(5-chloropyridin-2-y                                                         loxy)piperidino                                                                85.1-89.4 441.2 M + H        226 2(R) 2-propyl H 4-(4-fluorobenzoyl)piperidino 171.5-172.4 402 M + H        227 2(R) methyl H 8-chloro-1,2,3,4-tetrahydro-γ-carbolino                                                                  97.4-108 373 M + H                                                              228 2(R) methyl                                                               (diphenylmethyl)ethyl                                                          4-(chlorobenzoyl)piper                                                         idino  584.1 M + H                                                              229 2(RS) H phenyl                                                            4-(5-chloropyridin-2-y                                                         loxy)piperidino 61-64                                                          441 M + H                    230 (R) 4-fluorophenyl H 4-(4-fluorophenyl)piperidino 90-92 426 M + H                                                             231 (R) 4-(benzyloxyc                                                         arbo- H 4-(4-chlorophe                                                         nyl)piperazino 65-69                                                           554.2 M + H                    nylamino)butyl                                                             __________________________________________________________________________      and are named as:                                                              1. Nhydroxy-2-(R)-[benzyl(piperidine-1-sulfonyl)amino3-methylbutyramide.       5. Nhydroxy-2-[benzyl(4-chloropiperidine-1-sulfonyl)amino]acetamide.           15.                                                                            Nhydroxy-2-(RS)-{methyl[4(4-chlorophenyl)piperazine-1-sulfonyl]amino}acet     mide trifluoroacetate salt.                                                     23.                                                                            Nhydroxy-2-{(4(4-chlorophenyl)piperazine-1-sulfonyl]amino}propionamide.        33. Nhydroxy-2-{(4(3-chlorophenyl)piperazine-1-sulfonyl]amino}acetamide.       41.                                                                            Nhydroxy-2-(RS)-{[4(4-chlorophenyl)piperazine-1-sulfonyl]amino}butyramide      50.                                                                            Nhydroxy-2-(R)-{(4(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino3-meth     lbutyramide.                                                                    51.                                                                            Nhydroxy-2-(R)-{[4(4-chlorophenyl)piperazine-1-sulfonyl]amino3-methylbuty     amide.                                                                          54.                                                                            Nhydroxy-2-[4(5-trifluoromethylpyridin-2-yl)piperazine-1-sulfonyl]amino}a     etamide.                                                                        57.                                                                            Nhydroxy-2-(R)-{[4(4-chlorophenoxy)piperidine-1-sulfonyl]amino}propionami     e.                                                                              59.                                                                            Nhydroxy-2-(R)-{[4(4-chlorophenoxy)piperidine-1-sulfonyl]amino3-methylbut     ramide.                                                                         62.                                                                            Nhydroxy-2-(R)-{[4(4-chlorophenyl)piperazine-1-sulfonyl]amino3-methyl-3-m     thylthiobutyramide.                                                             66.                                                                            Nhydroxy-2-(R)-{[4(4-chlorobenzylcarbamoyl)methyl]piperidine1-sulfonyl]am     no}propionamide.                                                                74.                                                                            Nhydroxy-2-(R)-{[4(4-benzyloxyphenyl)piperazine-1-sulfonyl]amino3-methylb     tyramide.                                                                       78.                                                                            Nhydroxy-2-(R)-{pyridin3-ylmethyl-[4(phenoxy)piperidine-1-sulfonyl]amino3     methylbutyramide.                                                               84.                                                                            Nhydroxy-2-(R)-{[(4benzyl-4-hydroxy)piperidine-1-sulfonyl]amino3-methylbu     yramide.                                                                        90.                                                                            Nhydroxy-2-(RS)-{methyl[4(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amin     3-benzyloxypropionamide.                                                        93.                                                                            Nhydroxy-2-(R)-{[4(4-chlorobenzoyl)piperidine-1-sulfonyl]amino3-phenylthi     propionamide.                                                                   96.                                                                            Nhydroxy-2-(R)-{{4[4(pyridin-4-ylmethyloxy)phenyl]piperazine1-sulfonyl}am     no3-methylbutyramide.                                                           100.                                                                           Nhydroxy-2-(R)-{[4(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino3-m     thybutyramide.                                                                  103.                                                                           Nhydroxy-2-(R)-{[4(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino3-(4-h     droxyphenyl)propionamide.                                                       114.                                                                           Nhydroxy-2-(R)-{[4(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino3-(pyr     din-2-ylthio)propionamide.                                                      125.                                                                           Nhydroxy-2-(S)-{[4(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}propionami     e.                                                                              136.                                                                           Nhydroxy-2-(R)-{[4(5-phenylthiazol-2-yl)piperidine-1-sulfonyl]amino3-meth     butyramide.                                                                     148.                                                                           Nhydroxy-2-(R)-{[4(4-phenoxybenzoyl)piperidine-1-sulfonyl]amino}propionam     de.                                                                             159.                                                                           Nhydroxy-2-(R)-{[4(methyl-4-chlorobenzoylaminocarbonyl)piperazine-1-sulfo     yl]amino}propionamide                                                           170.                                                                           Nhydroxy-2-(R)-{[4(2-phenylbenzoxazol-5-yl)piperazine-1-sulfonyl]amino3-m     thybutyramide.                                                                  183.                                                                           Nhydroxy-2-(R)-{[4(6-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino3-m     thybutyramide.                                                                  196.                                                                           Nhydroxy-2-(RS)-{2N,N-dimethylaminoethyl-[4(phenyl)piperidine-1-sulfonyl]     mino}acetamide.                                                                 207.                                                                           Nhydroxy-2-(R)-{[4(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino2-c     clohexylacetamide.                                                              213.                                                                           Nhydroxy-2-(R)-{[4(4-phenoxyphenylaminocarbonyl)piperazine-1-sulfonyl]ami     o}propionamide.                                                                 224.                                                                           Nhydroxy-2-(R)-{[4(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}valer     mide.                                                                           230.                                                                           Nhydroxy-2-(R)-{[4(4-fluorophenyl)piperidine-1-sulfonyl]amino2-(4-fluorop     enyl)acetamide.                                                           

II. Compounds of formula (I) where R² =hydrogen, R¹⁰ =--NR¹¹ OR¹² where R¹¹ and R¹² are hydrogen, and other groups are as defined below are:

    __________________________________________________________________________     CPD                                                                               Stereo-                                                                       #  chem R.sup.1 CNR.sup.3 --NR.sup.20 R.sup.21 = heterocycloamino group                                                       M. Pt° C. Mass                                                          Spec.                         __________________________________________________________________________     232                                                                               2(R)                                                                               piperidino       pyrrolidino        142-144                               233 2(RS) piperidino piperidino 123-125                                        234 2(RS) piperidino 4-(4-chlorophenyl)piperazino  403 M + H                   235 2(R) piperidino 4-(4-fluorophenyl)piperazino 105-107                       236 2(RS) piperidino 4-benzylpiperazino 138-141                                237 2(RS) piperidino 4-(pyridin-2-yl)piperazino  370 M + H                     238 2(RS) piperidino 4-phenoxypiperidino 106-108                               239 2(RS) piperidino 4-phenylthiopiperidino  400.13                            240 2(RS) piperidino 4-(pyridin-4-ylthio)piperidino  401.13                    241 2(RS) piperidino 4-(pyridin-2-ylthio)piperidino                            242 2(R) piperidino 4-(4-chlorobenzoyl)piperidino 84.4-86.4 430 M + H                                                          243 2(R) pyrrolidino                                                          4-(4-chlorobenzoyl)piperi                                                      dino  416 M + H                 244 2(S) 2,2-dimethylthiomorpholino 4-(4-chlorobenzoyl)piperidino                                                             476.1 M + H                     245 2(R) piperidino 4-(pyridin-4-ylthio)piperidino  401.1 M+                   246 2(RS) piperidino 4-(phenylthio)piperidino  400.1 M+                        247 2(R) 3-(S)-(methoxycarbonyl)piperidino 4-(4-chlorobenzoyl)piperidino                                                        488 M + H                     248 2(S) 2,2-dimethylthiomorpholino 4-(5-chloropyridin-2-yl)piperazino                                                        126-131 450.1 M + H                                                             249 2(RS) 1,2,3,4-tetrah                                                      ydroisoquinolino                                                               4-(4-chlorophenyl)piperaz                                                      ino 166.6-167.4 452.1                                                          M+H                             250 2(RS) piperazino 4-(4-chlorobenzoyl)piperidino.TFA salt  431 M + H                                                         251 2(RS) 4-(cyclopropyl                                                      methyl)piperazino                                                              4-(4-chlorobenzoyl)piperi                                                      dino  485 M + H                 252 2(R) 3-azabicycl[3.1.0]-cyclohexyl 4-(4-chlorobenzoyl)piperidino                                                          428 M + H                       253 2(RS) 4-(2-N,N-dimethylaminoethyl)- 4-(4-chlorobenzoyl)piperidino                                                         502.2 M + H                       piperazino                                                                   254 2(RS) piperidino 4-(5-fluoroindol-3-yl)piperidino  425 M + H                                                               255 2(RS) 4-acetylpipera                                                      zino 4-(4-chlorobenzoyl)p                                                      iperidino  473 M + H                                                            256 2(RS) piperidino                                                          4-(6-chloroindol-3-yl)pip                                                      eridino 143-151 441 M +                                                        H                               257 2(R) piperidino 4-(4-bromobenzoyl)piperidino  474 M + H                    258 2(RS) 4-(pyridin-2-ylcarbonyl)piperazino 4-(4-chlorobenzoyl)piperidi                                                      no  536.2 M + H                 259 2(RS) 4-(thiophen-2-ylcarbonyl)piperazino 4-(4-chlorobenzoyl)piperid                                                      ino  541 M + H                  260 2(RS) 4-(benzylaminocarbonyl)piperazino 4-(4-chlorobenzoyl)piperidin                                                      o  564.2 M + H                  261 2(RS) 4-cyclohexanoylpiperazino 4-(4-chlorobenzoyl)piperidino                                                             541.1 M + H                     262 2(RS) 4-formylpiperazino 4-(4-chlorobenzoyl)piperidino  459 M + H                                                          263 2(RS) 4-(pyrrolidin-                                                      2-one-5-carbonyl)-                                                             4-(4-chlorobenzoyl)piperi                                                      dino  542 M + H                   piperazino                                                                   264 2(RS) 4-[2-(S)-amino-3-methylbutanoyl]- 4-(4-chlorobenzoyl)pipendino                                                        530 M + H                       piperazino TFA salt                                                          265 2(RS) 4-(N-methylaminocarbonyl)piperazino 4-(4-chlorobenzoyl)piperid                                                      ino  488 M + H                  266 2(RS) 4-propanoylpiperazino 4-(4-chlorobenzoyl)piperidino  487.1 M                                                        + H                             267 2(R) morpholino 4-(4-chlorobenzoyl)piperidino 119-123.9 432.1 M + H        268 2(R) 1,2,3,4-tetrahydroisoquinolino 4-(4-chlorobenzoyl)piperidino                                                         478 M + H                       269 2(RS) 4-(phenylaminocarbonyl)piperazino 4-(4-chlorobenzoyl)piperidin                                                      o  550 M + H                    270 2(RS) piperidino isoindolin-2-yl 118-121                                   271 2(R) piperidino 8-fluoro-1,2,3,4-tetrahydro-β-carbolino                                                               272 2(RS) piperidino                                                          4-(5-chlorobenzimidazol-1                                                      -yl)piperidino  442 M +                                                        H                               273 2(RS) piperidino 4-(5-chloroindol-3-yl)piperidino 117.8-143.9 441 M                                                       + H                             274 2(RS) piperidino 4-(5-chlorobenzotriazol-1-yl)piperidino  443 M + H        275 2(RS) 4-(benzyloxycarbonyl)piperazino 4-(5-fluoroindol-3-yl)piperidi                                                      no 85.7-89.7 560 M + H                                                          276 2(RS) 4-(benzyloxyca                                                      rbonyl)piperazino                                                              4-(6-chloroindol-3-yl)pip                                                      eridino 98.2-102.2 576 M                                                       + H                             277 2(RS) 4-acetylpiperazino 4-(6-methylindol-3-yl)piperidino  464 M +                                                        H                               278 2(RS) 4-(methoxycarbonylmethyl)piperazino 4-(4-chlorobenzoyl)piperid                                                      ino  503 M + H                  279 2(RS) piperidino 4-(5-fluoroindol-3-ylcarbonyl)piperidino                  280 2(RS) piperidino 4-(6-chloropyridin-2-yloxy)piperidino 129.2-129.4                                                        419 M + H                       281 2(RS) piperidino 4-(5-chloropyridin-2-yloxy)piperidino 141.1-141.8                                                        419 M + H                       282 2(RS) piperidino 4-(5-chloropyridin-2-yl)piperazino 127.2-131.6 404                                                       M + H                           283 2(RS) 4-(aminomethylcarbonyl)piperazino 4-(4-chlorobenzoyl)piperidin                                                      o TFA salt  488 M + H                                                           284 2(RS) 4-(methoxycarb                                                      onyl)piperazino 4-(4-chlo                                                      robenzoyl)piperidino                                                           489 M + H                       285 2(RS) piperidino 4-(4-chloroindol-3-yl)piperidino 143-147 441 M + H        286 2(RS) piperidino 4-(6-fluorobenzisoxazol-3-yl)piperidino 145.8-146.9                                                       427.1 M + H                    287 2(R) piperidino 4-(6-fluoroindol-3-yl)piperidino 110-144.2 425 M +                                                        H                               288 2(RS) piperidino 4-(5-methoxyindol-3yl)piperidino  437 M + H                                                               289 2(RS) piperidino                                                          4-(4-chloro-2-methyl)pipe                                                      razino 156-158.5 416 M+                                                         290 2(RS) 4-formylpipera                                                      zino 4-(4-methylbenzoyl)p                                                      iperidino  439.2 M + H                                                          291 2(RS) piperidino                                                          4-(2,3-dimethylphenyl)pip                                                      erazino 128-129.5 397 M                                                        + H                             292 2(RS) piperidino 4-(5-hydroxyindol-3-yl)piperidino  423 M + H                                                              293 2(RS) piperidino                                                          4-(4-chloro-3-trifluorome                                                      thylphenyl)- 135.4-136                                                         470 M + H                          piperidino                                                                  294 2(R) piperidino 4-(5-cyanoindol-3-yl)piperidino  432 M + H                 295 (RS) piperidino 4-[(6-fluoroisothiazol-3-yl)piperidino 170.8-172                                                          443 M + H                       296 (RS) piperidino 4-(5-chloroindol-1-yl)piperidino  441 M + H                                                                297 (RS) piperidino                                                           4-(6-chlorobenz-1,2,3-tri                                                      azol-1-yl)- 165-167 443                                                        M + H                              piperidino                                                                  298 (R) 4-(N,N-dimethylaminocarbonyl)- 4-(4-chlorobenzoyl)piperidino                                                          502 M + H                         piperazino                                                                   299 (R) piperidino 4-(4,5,6,7-tetrafluoroindol-3-yl)piperidino  479.13                                                        M + H                           300 (RS) piperidino 4-(diphenylmethyl)piperidino 103.7-145 458.21 M + H        301 (RS) piperidino 4-(6-chlorobenzimidazol-1-yl)piperidino 128.8-132.4                                                       442 M + H                       302 (RS) 4-(tert-butylaminocarbonyl)piperazino 4-(5-fluoroindol-3-yl)pip                                                      eridino  525.22 M + H                                                           303 (RS) 4-(benzyloxycar                                                      bonyl)piperazino                                                               4-(1-trimethylsilylethyls                                                      ulfonyl-4,5,6,7-                                                               124.8-130.4 778.2 M + H                                                            tetrafluoroindol-3-yl                                                      )piperidino                     304 (RS) 4-(benzyloxycarbonyl)piperazino 4-(4,5,6,7-tetrafluoroindol-3-y                                                      l)piperidino 151.5-157.7                                                       614.16 M + H                    305 (RS) 4-methoxycarbonylpiperazino 4-(5-fluoroindol-3-yl)piperidino                                                         141.2-148.7 484.16 M + H        306 (RS) 4-(tetrahydropyran-4-ylcarbonyl)- 4-(5-fluoroindol-3-yl)piperid                                                      ino 141-200 538.21 M + H          piperazino                                                                   307 (R) piperidino 4-(5-acetylaminoindol-3-yl)piperidino 142-145 464 M                                                        + H                             308 (RS) 4-[2(S)-amino-3-methylbutyryl)- 4-(6-fluoroindol-3-yl)piperidin                                                      o  525 M + H                      piperazino                                                                   309 (R) 4-(N,N-dimethylaminocarbonyl)- 4-(4,5,6,7-tetrafluoroindol-3-yl)                                                      piperidino 181-184                                                             551.17 M + H                      piperazino                                                                   310 (R) 4-(cyclopropylmethyl)piperazino 4-(6-fluoroindol-3-yl)piperidino                                                        480.20 M + H                  311 (RS) 4-(N,N-dimethylaminosulfonyl)- 4-(5-fluoroindol-3-yl)piperidino                                                       111.5-113.7 533 M + H                                                            piperazino                   312 (RS) 4-[bis(N,N-dimethylamino)- 4-(6-fluoroindol-3-yl)piperidino                                                          560.22 M + H                      phosphoryl]piperazino                                                        313 (R) 4-(N,N-dimethylaminocarbonyl)- 4-(4-fluorophenyl)piperidino                                                           89.8-112.5 458 M + H                                                              piperazino                   314 (R) piperidino 1,2,3,4-tetrahydro-β-carbolino 92.2-141.7 379 M                                                       + H                             315 (R) 4-(N,N-dimethylaminosulfonyl)- 4-(4-chlorobenzoyl)piperidino                                                          538.11 M + H                      piperazino                                                                   316 (R) 4-(morpholin-4-ylcarbonyl)piperazino 4-(4-chlorobenzoyl)piperidi                                                      no  544.16 M + H                                                                317 (R) 4-(N-tert-butyla                                                      minocarbonyl)- 4-(5-cyano                                                      indol-3-yl)piperidino                                                          142-200 352.23 M + H                                                              piperazino  decomp.                                                          318 (R) piperidino                                                            4-[5-(4-chlorophenyl)pyrr                                                      ol-2-yl]piperidino                                                             91.4-122.4 467 M + H                                                            319 (R) 4-(1,4-pyrazin-2                                                      -ylcarbonyl)piperazino                                                         4-(4-chlorobenzoyl)piperi                                                      dino  538.13 M + H                                                              320 (R) 4-(pyridin-3-ylm                                                      ethyl)piperazino                                                               4-(4-chlorobenzoyl)piperi                                                      dino  522.15 M + H                                                              321 (R) 4-(morpholin-4-y                                                      lcarbonyl)piperazino                                                           4-(5-cyanoindol-3-yl)pipe                                                      ridino 144-200 546.21 M                                                        + H                             322 (RS) 4-(2,2,2-trifluoroethyl)piperazino 4-(4-fluorophenyl)piperidino                                                       142.1-143.4 469 M+H                                                            323 (R) 4-(aminocarbonyl                                                      methyl)piperazino                                                              4-(4-chlorobenzoyl)piperi                                                      dino  488.13 M + H                                                              324 (R) piperidino                                                            4-(5-cyano-1-methylsulfon                                                      ylindol-3-yl)- 143.3-143.                                                      9 510.1 M + H                      piperidino                                                                  325 (R) 2,2,-dimethylthiomorpholino 4-(5-cyanoindol-3-yl)piperidino                                                           478 M + H                       326 (R) piperidino 3-(4-chlorophenoxy)azetidino  397.13 M + H                  327 (R) piperidino 4-(5-fluoro-2-hydroxylaminobenzoyl)-  457.15 M + H                                                             piperidino                  328 (RS) piperidino 4-(2-amino-5-fluorobenzoyl)piperidino  429.16 M + H        329 (R) piperidino 4-[1-(4-fluorophenyl)pyrrol-3-yl]piperidino  451 M +                                                       H                               330 (R) 4-(1,4-pyrazin-2-ylcarbonyl)piperazino 4-(5-cyanoindol-3-yl)pipe                                                      ridino  537 M - H                                                               331 (R) 4-(S)-hydroxypip                                                      eridino 4-(4-chlorobenzoy                                                      l)piperidino  446 M + H                                                         332 2(RS) 4-benzyloxycar                                                      bonylpiperazino 4-(6-chlo                                                      roindol-3-yl)piperidino                                                        98.2-102.2                      333 2(RS) 4-benzyloxycarbonylpiperazino 4-(1-trimethylsilylethylsulfonyl                                                      -6- 104.2-                         chloroindol-3-yl)piperidino 108.2                                           334 2(RS) 4-benzyloxycarbonylpiperazino 4-(1-trimethylsilylethylsulfonyl                                                      -6- 98.4-103.7                     fluoroindol-3-yl)piperidino                                                 335 2(RS) 4-benzyloxycarbonylpiperazino 4-(5-fluoroindol-3-yl)piperidino                                                       85.7-89.7                      336 2(RS) 4-acetylpiperazino 4-(6-methylindol-3-yl)piperidino                __________________________________________________________________________      and are named as:                                                              232. Nhydroxy-1-(pyrrolidine-1-sulfonyl)piperidine-2-(R)-carboxamide.          234.                                                                           Nhydroxy-1-[4(4-chlorophenyl)piperazine-1-sulfonyl]piperidine2-(RS)-carbo     amide.                                                                          237.                                                                           Nhydroxy-1-[4(pyridin-2-yl)piperazine-1-sulfonyl]piperidine2-(RS)-carboxa     ide.                                                                            238.                                                                           Nhydroxy-1-[4(4-phenoxy)piperidine-1-sulfonyl]piperidine2-(RS)-carboxamid      239.                                                                           Nhydroxy-1-[4(4-phenylthio)piperidine-1-sulfonyl]piperidine2-(RS)-carboxa     ide.                                                                            240.                                                                           Nhydroxy-1-[4(pyridin-4-ylthio)piperidine-1-sulfonyl]piperidine2-(RS)-car     oxamide.                                                                        249.                                                                           Nhydroxy-1-[4(4-chlorophenyl)piperazine-1-sulfonyl1,2,3,4-tetrahydroisoqu     noline-2-(RS)-carboxamide.                                                      258.                                                                           Nhydroxy-1-[4(4-chlorophenyl)piperidine-1-sulfonyl4-(pyridin-2-ylcarbonyl     piperazine-2-(RS)-carboxamide.                                                  267.                                                                           Nhydroxy-1-[4(4-chlorobenzoyl)piperidine-1-sulfonyl]morpholine2-(R)-carbo     amide.                                                                          277.                                                                           Nhydroxy-4-acetyl-1-[4(6-methylindol-3-yl)piperidine-1-sulfonyl]piperazin     2-(RS)-carboxamide.                                                             289.                                                                           Nhydroxy-1-[4(4-chloro-2-methyl)piperazine-1-sulfonyl]piperidine2-(RS)-ca     boxamide.                                                                       299.                                                                           Nhydroxy-1-[4(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperid     ne2-(R)-carboxamide.                                                            310.                                                                           Nhydroxy-4-cyclopropylmethyl-1-[4(6-fluoroindol-3-yl)piperidine-1-sulfony     ]piperazine2-(R)-carboxamide.                                                   321.                                                                           Nhydroxy-4-(morpholin-4-ylcarbonyl)-1-[4(5-cyanoindol-3-yl)piperidine-1-s     lfonyl]piperazine2-(R)-carboxamide.                                             331.                                                                           Nhydroxy-1-[4(4-chlorobanzoyl)piperidine-1-sulfonyl4-(S)-hydroxypiperidin     -2-(R)-carboxamide.                                                       

III. Compounds of formula (I) where R³ =hydrogen, R¹⁰ =--NR¹¹ OR¹² where R¹¹ and R¹² are hydrogen, and other groups are as defined below are:

    __________________________________________________________________________     CPD                                                                              #  R.sup.1 R.sup.2 R.sup.1 CR.sup.2 --NR.sup.20 R.sup.21 = heterocycloam                                                 ino group M. Pt. ° C.                                                   Mass Spec.                         __________________________________________________________________________     337        cyclopentyl                                                                             4-phenoxypiperidino                                                                             124.5-125.5                                                                           384 M + H                            338   cyclopentyl 4-(4-chlorophenyl)piperazino 135.3 efferves. 403.12 M                                                  + H                                  339   tetrahydropyran-4-yl 4-(4-chlorophenyl)piperazino 192.5-192.7 419                                                  M + H                                340   cyclopropyl 4-(5-chloropyridin-2-y)piperazino 152.6 efferves.                                                      376.08 M + H                         341   cyclopropyl 4-(4-chlorophenyl)piperazino 169.9 efferves. 375.09 M                                                  + H                                  342   cyclohexyl 4-(5-chloropyridin-2-yl)piperazino 116.1 efferves.                                                      418.13 M + H                         343   tetrahydropyran-4-yl 4-(5-trifluoromethylpyridin-2-yl)- 192.5-192.                                                 8 454 M + H                              piperazino                                                                 344   tetrahydropyran-4-yl 4-(5-chloropyridin-2-yl)piperazino 186.9 420                                                  M + H                                345   cyclohexyl 4-(4-chlorophenyl)piperazino 146.1-146.6 417.1 M + H                                                     346   tetrahydropyran-4-yl                                                    4-[4-(benzyloxy)phenyl]piperaz                                                 ino 186 efferves. 491.1 M + H        347   tetrahydropyran-4-yl 4-phenoxypiperidino 128 efferves. 400.15 M +                                                  H                                    348   cyclohexyl 4-(5-trifluoromethylpyridin-2-yl)- 126.5-148 452.1 M +                                                  H                                        piperazino decomp.                                                         349   piperidin-4-yl 4-(4-chlorobenzoyl)piperidino. HCl salt 169.6-170.6       350   1-methylsulfonyl- 4-(4-chlorobenzoyl)piperidino  523 M + H                                                             piperidin-4-yl                   351 methyl methyl  4-(4-chlorobenzoyl)piperidino 185.7-186.7                   352 methyl methyl  4-(5-chloropyridin-2-yl)piperazino 167.2-167.5 378.1                                                  M + H                                353   tetrahydropyran-4-yl 4-(5-chloropyridin-2-yloxy)piperidino  435.1                                                  M + H                                354 methyl methyl  4-[4-(benzyloxy)phenyl]piperazino 153.7-155.3 449.18                                                  M + H                              __________________________________________________________________________      and are named as follows:                                                      337.                                                                           Nhydroxy-1-{[(4phenoxy)piperidine-1-sulfonyl]amino}cyclopentane1-carboxam     de.                                                                             339.                                                                           Nhydroxy-4-{[4(4-chlorophenyl)piperazine-1-sulfonyl]amino}tetrahydropyran     -carboxamide.                                                                   347.                                                                           Nhydroxy-4-{[4(4-phenoxy)piperidine-1-sulfonyl]amino}tetrahydropyran4-car     oxamide.                                                                        351.                                                                           Nhydroxy-2-{[4(4-chlorobenzoyl))piperidine-1-sulfonyl]amino2-methylpropio     amide.                                                                    

IV. Compounds of formula (I) where R² =hydrogen, R¹⁰ =--NR¹¹ OR¹² where R¹¹ and R¹² are hydrogen, and other groups are as defined below are:

    __________________________________________________________________________     CPD                                                                               Stereo                                                                        #  chem R.sup.1 R.sup.1 CNR.sup.3 R.sup.3 R.sup.20 R.sup.21 M. Pt.                                                       ° C. Mass Spec.             __________________________________________________________________________     355     H         benzyl                                                                             methyl                                                                             benzyl            363 M+                               356 2(RS) 2-propyl  benzyl methyl 3-phenylpropyl  434 M + H                    357 2(RS) 2-propyl  benzyl methyl (4-biphenyl)methyl 136.5-138.5 482 M                                                   + H                                  358 2(RS) 2-propyl  benzyl methyl benzyl 128.2-129 406 M + H                   359 2(RS) 2-propyl  benzyl H benzyl  391 M+                                    360 2(RS) 2-propyl  benzyl H methyl  316 M + H                                 361 2(RS) 2-propyl  benzyl methyl 3-(4-biphenyl)propyl 68-71 509 M+                                                       362 2(RS) 2-propyl  benzyl                                                    methyl 2-phenylethyl  419 M+                                                    363 2(R)  piperidino  methyl                                                  benzyl  328 M + H                    364 2(R) methyl  H H 3-(5-fluoroindol-l-yl)propyl 157-158                    __________________________________________________________________________      and are named as:                                                              358.                                                                           Nhydroxy-2-(RS)-{[benzyl(methyl-benzyl-aminosulfonyl)amino3-methylbutyram     de.                                                                             360.                                                                           Nhydroxy-2-(RS)-{[benzyl(methyl-aminosulfonyl)amino3-methylbutyramide.         363.                                                                           Nhydroxy-1-[(methylbenzyl-aminosulfonyl)amino]piperidine2-(R)-carboxamide

V. Compounds of formula (I) where R² =H, R¹⁰ =--NR¹¹ OR¹² and other groups are as defined below are:

    __________________________________________________________________________     CPD                                                                               Stereo-           --NR.sup.20 R.sup.21 = heterocycloamino                     # chem R.sup.1 CNR.sup.3 group R.sup.11 R.sup.12 Mass Spec.                  __________________________________________________________________________     365                                                                               (RS)                                                                               4-formylpiperazino                                                                           4-(5-fluoroindol-3-yl)piperidino                                                             H       benzyl                                                                             544 M + H                         366 (R) piperidino 4-(4,5,6,7-tetrafluoroindol-3-yl)- H benzyl 569 M +                                                      H                                    piperidino                                                                  367 (RS) 4-(methoxycarbonyl)piperazino 4-(5-fluoroindol-3-yl)piperidino                                                     H benzyl 574.21 M + H                                                           368 (RS) 4-(tetrahydropyra                                                    n-4-yl- 4-(5-fluoroindol-3-                                                    yl)piperidino H benzyi                                                         628.26 M + H                        carbonyl)piperazino                                                          369 (R) 4-(tert-butylaminocarbonyl)- 4-(4,5,6,7-tetrafluoroindol-3-yl)-                                                     H benzyl 669.24 M + H                                                             piperazino piperidino                                                        370 (R) 4-(N,N-dimethylami                                                    no- 4-(4,5,6,7-tetrafluoroi                                                    ndol-3-yl)- H benzyl                                                           641.21 M + H                        carbonyl)piperazino piperidino                                               371 (R) piperidino 4-(4,5,6,7-tetrafluoroindol-3-yl)- morpholin-4-yl- H                                                     578.20 M + H                         piperidino methyl                                                           372 (R) piperidino 4-(5-fluoroindol-3-yl)piperidino methyl H 425 M + H                                                       373 (R) 4-(N,N-dimethylami                                                    no- 4-(5-cyanoindol-3-yl)pi                                                    peridino H benzyl 594.24 M                                                     + H                                 carbonyl)piperazino                                                          374 (R) piperidino 4-(5-cyanoindol-3-yl)piperidino methyl methyl 460 M                                                      + H                             __________________________________________________________________________      and are named as:                                                              365.                                                                           Nbenzyloxy-4-formyl-1-[4(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperaz     ne2-(RS)-carboxamide.                                                           372.                                                                           Nhydroxy-N-methyl-1-[4(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidin     2-(R)-carboxamide.                                                        

VI. Compounds of formula (I) where R² =H, R¹⁰ =--NR¹¹ OR¹² where R¹¹ and R¹² are hydrogen and other groups are as defined below are:

    __________________________________________________________________________     CPD                                                                               Stereo-                                                                       #  chem R.sup.1 CNR.sup.3 --NR.sup.20 R.sup.21 = substituted tetrahydrop                                                     yridine ring M. Pt.                                                            ° C. Mass Spec.         __________________________________________________________________________     375                                                                               (RS)                                                                               piperidino  4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine                                                         137.8-138.1                            376 (RS) piperidino 4-(4-chloro-3-trifluoromethylphenyl)-1,2,3,6-                                                            -137.4                              tetrahydropyridine                                                          377 (RS) piperidino 4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine                                                           107.6-108.1                      378 (RS) piperidino 4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridi                                                     ne 59.8-105.2 418 M + H                                                         379 (RS) piperidino                                                           4-(5-chloroindol-3-yl)-1,2                                                     ,3,6-tetrahydropyridine                                                        113.2-157.6 439 M + H                                                           380 (RS) piperidino                                                           4-(5-fluoroindol-3-yl)-1,2                                                     ,3,6-tetrahydropyridine                                                        100-102 423 M + H                                                               381 (RS) 4-benzyloxycarbo                                                     nyl- 4-(4-fluoro-3-methylp                                                     henyl)-1,2,3,6-tetrahydrop                                                     yridine 67-70 533 M + H                                                           piperazino                    382 (RS) 4-acetylpiperazino 4-(4-fluoro-3-methylphenyl)-1,2,3,6-tetrahyd                                                     ropyridine 94-98 441 M +                                                       H                                383 (RS) 4-(N,N-dimethylamino- 4-(4-fluoro-3-methylphenyl)-1,2,3,6-tetra                                                     hydropyridine  470 M +  H          carbonyl)piperazino                                                          384 (RS) 4-tert-butoxycarbonyl- 4-(4-fluoro-3-methylphenyl)-1,2,3,6-tetr                                                     ahydropyridine 122-126                                                         499 M + H                          piperazino                                                                   385 (RS) piperidino 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine                                                             145.5-147 444 M + H                                                             386 (RS) piperidino                                                           4-(4-fluorophenyl)-1,2,3,6                                                     -tetrahydropyridine                                                            159-161 384 M + H                                                               387 (R) piperidino                                                            4-(4-fluorophenyl)-1,2,3,6                                                     -tetrahydropyridine                                                            148.2-149 384 M + H                                                             388 (RS) piperidino                                                           4-phenyl-1,2,3,6-tetrahydr                                                     opyridine 144.5-145 366 M                                                      + H                              389 (RS) 4-(N,N-dimethylamino- 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyri                                                     dine 87.5-91 456 M + H                                                            carbonyl)piperazino                                                          390 (R) 4-(N,N-dimethylam                                                     ino- 4-(4-fluorophenyl)-1,                                                     2,3,6-tetrahydropyridine                                                       90.5-95 456 M + H                                                                 carbonyl)piperazino                                                          391 (RS) piperidino                                                           4-(4-methylphenyl)-1,2,3,6                                                     -tetrahydropyridine                                                            123.2-125.8 380 M + H                                                           392 (RS) 4-(N,N-dimethyla                                                     mino- 4-(4-chlorophenyl)-1                                                     ,2,3,6-tetrahydropyridine                                                      84-116.8 472 M + H                                                                carbonyl)piperazino                                                          393 (R) 2,2-dimethylthio-                                                      4-(4-fluorophenyl)-1,2,3,                                                     6-tetrahydropyridine                                                           176.7-177.5 430 M + H                                                             morpholino                    394 (RS) 4-(2,4-difluorophenyl- 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyr                                                     idine  590 M + H                   aminocarbonyl)piperazino                                                     395 (R) piperidino 4-(3,4-difluorophenyl)-1,2,3,6-tetrahydropyridine                                                         57-61.5 402 M + H                                                               396 (RS) 4-(N,N-dimethyla                                                     mino- 4-(4-fluorophenyl)-1                                                     ,2,3,6-tetrahydropyridine                                                      120.3-121 492 M + H                                                               sulfonyl)piperazino                                                          397 (RS) 4-(morpholin-4-y                                                     l- (4-4-fluorophenyl)-1,2,                                                     3,6-tetrahydropyridine                                                         102-105 498 M + H                                                                 carbonyl)piperazino                                                          398 (RS) 4-(2,2,2-trifluo                                                     roethyl)- 4-(4-fluoropheny                                                     l)-1,2,3,6-tetrahydropyrid                                                     ine 54.3-62.6 467 M + H                                                           piperazino                    399 (RS) 4-[bis(N,N-dimethylamino- 4-(4-fluorophenyl)-1,2,3,6-tetrahydro                                                     pyridine 98-102 519 M + H          phosphoryl)]piperazino                                                       400 (R) 4-(N,N-dimethylamino- 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyrid                                                     ine 90.4-93.1 470 M + H                                                           carbonyl)piperazino         __________________________________________________________________________      and are named as:                                                              375.                                                                           Nhydroxy-1-[4(4-chlorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piper     dine2-(RS)-carboxamide.                                                         381.                                                                           Nhydroxy-4-benzyloxycarbonyl-1-[4(4-fluoro-3-methylphenyl)-1,2,3,6-tetrah     dropyridine-1-sulfonyl]piperazine2-(RS)-carboxamide.                            393.                                                                           Nhydroxy-4-[4(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl2,2-di     ethylthiomorpholine-3-(R)-carboxamide.                                          399.                                                                           Nhydroxy-4-[bis(N,Ndimethylaminophosphoryl)1-[4(4-fluorophenyl)-1,2,3,6-t     trahydropyridine-1-sulfonyl]piperazine2-(RS)-carboxamide.                 

VII. Compounds of formula (I) where R² =H, R¹⁰ =--NR¹¹ OR¹² where R¹¹ and R¹² are hydrogen and other groups are as defined below are:

    __________________________________________________________________________     CPD                                                                               Stereo-                                                                       #  chem R.sup.1 --NR.sup.20 R.sup.21 = substituted tetrahydropyridine                                                  ring M. Pt.° C. Mass                                                    Spec.                                __________________________________________________________________________     401                                                                               (R) methyl   4-(4-ch1oropheny1)-1,2,3,6-tetrahydropyridine                                                       90.7-93                                                                             360 M + H                              402 (R) 2-propyl 4-(4-chloro-3-methylphenyl)-1,2,3,6- 65.2-82.2 386 M +                                                H                                         tetrahydropyridine                                                          403 (R) 4-(benzyloxycarbon- 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin                                               e 72-79 551.2 M + H                      yl)aminobutyl                                                                404 (R) phenyl 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine 79-82.5                                                   406 M + H                              405 (R) 4-(benzyloxycarbon- 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin                                               e 61.9-65.6 535 M + H                    ylamino)butyl                                                                406 (R) 2-propyl 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine 144-144.5                                                372 M + H                             407 (R) tert-butyl 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine                                                       110-114.8 386 M + H                    408 (R) 4-fluorophenyl 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine                                                   89.2-110 424 M + H                     409  4-fluorophenyl 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine                                                      76.5-79 440 M + H                    __________________________________________________________________________      and are named as:                                                              401.                                                                           Nhydroxy-2-(R)-1-[4(4-chlorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl     propionamide.                                                                   406.                                                                           Nhydroxy-2-(R)-1-[4(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl     -methylbutyramide.                                                        

VIII. Compounds of formula (I) where R² =H, R¹⁰ =--OH and other groups are as defined below are:

    __________________________________________________________________________     CPD                                                                               Stereo-                                  Mass                                 #  chem R.sup.1 R.sup.3 R.sup.1 CNR.sup.3 --NR.sup.20 R.sup.21 Spec.         __________________________________________________________________________     410                                                                               (RS)             piperidino                                                                          4-(4-fluoro-3-methylphenyl)-1,2,3,6-tetra-                                                        383 M + H                                 hydropyridine                                                             411 (RS)   piperidino 4-(3-chloro-4-fluorophenyl)-1,2,3,6- 403 M + H                                                           tetrahydropyridine                                                        412 (R) 4-(benzyloxycarbo- H                                                   4-(4-chlorophenyl)piperazino                                                  539 M + H                              nylamino)butyl                                                               413 (R) 2-propyl H  4-[4-(pyridin-4-ylmethyloxy)- 462 M + H                         phenyl]piperazino                                                         414 (R) methyl H  4-(4-chlorophenyl)piperazino 347 M+                          415 (R) methyl H  4-(4-chlorophenyl)piperidino 346 M + H                       416 (R) 2-propyl H  4-(5-chloropyridin-2-yloxy)piperidino 392 M + H                                                       417 (RS)   piperidino                                                         4-(6-fluorothiazol-3-yl)piperi                                                 dino 348 M+                          418 (R)   piperidino 4-(6-chloroindol-3-yl)piperidino 426 M + H                                                           419  H H  4-(4-fluorophenyl)p                                                 iperazino 432 M + H                  420  H H  4-(4-chlorophenyl)piperazino 333 M+                                  421 (RS)   piperidino 4-(5-chloroindol-1-yl)piperidino 426 M + H                                                          422 (RS)   piperidino                                                         4-(5-chloroindol-3-yl)piperidi                                                 no 426 M + H                         423  H benzyl  4-(4-chlorophenyl)piperazino 424 M + H                          424  H benzyl  4-methoxypiperidino 342 M+                                      425 (RS)   piperidino 4-(5-methylindol-3-yl)piperidino 406 M + H                                                          426 (R) 2-propyl H  4-[4-(pyr                                                 idin-3-ylmethyloxy)phenyl]-                                                    449 M + H                                 piperazino                                                                427 (RS)   piperidino 4-(1,2,3,4-tetrahydro-β-carbolino)piperidino        428 (R) n-propyl H  4-(5-chloropyridin-2-yl)piperazino 377.1 M +             __________________________________________________________________________                                                 H                                   and are named as:                                                              410.                                                                           1[4(4-fluoro-3-methylphenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperi     ine2-(RS)-carboxylic acid.                                                      413.                                                                           2(R)-{[4(pyridin-4-ylmethyloxyphenyl)piperazine-1-sulfonyl]amino3-methylb     tyric acid.                                                                     427.                                                                           1[4(1,2,3,4-tetrahydro-carbolino)piperidine-1-sulfonyl]piperidine2-(RS)-c     rboxylic acid.                                                            

IX. Compounds of formula (I) where R¹⁰ =--OH and other groups are as defined below are:

    __________________________________________________________________________     CPD                                                                               Stereo-                                                                       #  chem R.sup.1 R.sup.2 R.sup.3 R.sup.20 R.sup.21 Mass Spec.                 __________________________________________________________________________     429                                                                               (RS)                                                                               2-propyl                                                                            H benzyl methyl                                                                             4-biphenylmethyl                                                                         466 M+                                        430 (RS) H H benzyl methyl benzyl 348 M+                                       431 (R) methyl H benzyl H benzyl                                               432 (RS) 2-propyl H benzyl methyl 3-(4-biphenyl)propyl 494 M+                  433 (R) methyl H 2-phenylethyl H 2-phenylethyl                                 434 (RS) 2-propyl H benzyl methyl benzyl 391 M + H                             435 (RS) 2-propyl H benzyl methyl 2-phenylethyl 405 M + H                    __________________________________________________________________________      and are named as:                                                              429.                                                                           2(RS)-{benzyl[methyl(4-biphenylmethyl)aminosulfonyl]amino)3-methylbutyric      acid.                                                                          433. 2(R)-[2phenylethyl-(2-phenylethylaminosulfonyl)amino]propionic acid.      Miscellaneous compounds:                                                       436. A compound of formula (I) where, R.sup.10 = --NHOH, R.sup.1 and           R.sup.2 = hydrogen, R.sup.3 and R.sup.20 together = --(CH.sub.2).sub.2 --      and R.sup.21 = 4biphenylmethyl is named as                                     Nhydroxy-5-(biphenyl-4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-acetam     de. (361 M+).                                                                   437. A compound of formula (I) where, R.sup.10 = --NHOH, R.sup.1 and           R.sup.2 = hydrogen, R.sup.3 and R.sup.20 together = --(CH.sub.2).sub.2 --      and R.sup.21 = 4phenoxybenzoyl is named as                                     Nhydroxy-5-(4-phenoxybenzoyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-acetamide      (361 M+).                                                                

Preferred Embodiments

While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of formula (I) are preferred.

(I) Hydroxamic Acids and Their Derivatives

Compounds of formula (I) where R¹⁰ is --NR¹¹ OR¹².

Within this group a preferred group of compounds is that wherein R¹⁰ is --NHOH.

Within this preferred group, a more preferred group of compounds is that wherein:

R¹ is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, or heteroalkyl, more preferably 2-propyl, tert-butyl, 1-hydroxyethyl, tert-butoxymethyl, 2,2-dimethylpropyl, 2-methylpropyl, 1-methylpropyl, n-propyl, benzyl, phenyl, 4-fluorophenyl, cyclohexyl, (1-methyl-1-methylthio)ethyl, phenythiomethyl, benzylthiomethyl, thiophen-2-ylthiomethyl, pyridin-2-ylthiomethyl, 4-(benzyloxycarbonylamino)butyl, or benzyloxymethyl, most preferably 2-propyl, 1-methylpropyl, 2-methylpropyl, 2,2-dimethylpropyl, n-propyl, or 4-fluorophenyl;

R² is hydrogen; and

R³ is hydrogen, alkyl, aralkyl, heteroaralkyl, or heteroalkyl, preferably hydrogen, methyl, N,N-dimethylaminoethyl, pyridin-3-ylmethyl, benzyl, or 2-phenoxyethyl, most preferably hydrogen, N,N-dimethylaminoethyl, or pyridin-3-ylmethyl.

Within this group, particularly preferred compounds are those where the spatial arrangement of the groups at the carbon atom to which R¹ and R² are attached is as shown in FIG. 1 below. ##STR5##

Another more preferred group of compounds is that wherein R¹ and R² together with the carbon atoms to which they are attached form a carbocycle or heterocycle, preferably a carbocycle with a ring size between 3 to 6 carbon atoms, more preferably 5 or 6 carbon atoms, or a heterocycle of 6 ring atoms containing a single N, O, or S atom with the carbon to which R¹ and R² are attached being in the 4-position of the heterocycle, most preferably cyclopentyl, cyclohexyl, or piperidino where the nitrogen in the piperidino ring is optionally substituted with acyl, --SO₂ R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), or --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl); and

R³ is as described above.

Yet another more preferred group of compounds is that wherein R³ and R¹ together with the atoms to which they are attached form a heterocycloamino group, preferably a heterocycloamino group with a ring size of 6 ring atoms and optionally containing a second heteroatom selected from the group consisting of N, O, or S(O)_(n) (where n is an integer from 0-2), preferably at the 4-position with the nitrogen atom to which R³ is attached being in the 1-position of the heterocycloamino group. Representative heterocycloamino groups formed by R³ and R¹ include, but are not limited to, piperidino, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 2,2-dimethylthiomorpholino, or piperazino wherein the nitrogen at the 4-position of the piperazino ring is optionally substituted with alkyl, haloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, acyl, --COOR^(a) -(alkylene)-COOR^(a) (where R^(a) is alkyl), --SO₂ R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), --CONR'R", or -(alkylene)-CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), preferably acyl, haloalkyl, --SO₂ R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), or --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), more preferably acetyl, formyl, 2,2,2-trifluoroethyl, aminocarbonyl, tert-butylaminocarbonyl, N,N-dimethylaminocarbonyl, 2,4-difluorophenylaminocarbonyl, N,N-dimethylaminosulfonyl, bis(N,N-dimethylaminophosphoryl), morpholin-4-ylcarbonyl, morpholin-4-ylsulfonyl or 1,4-pyrazin-2-ylcarbonyl.

Within this group, particularly preferred compounds are those where the spatial arrangement of the groups at the carbon atom to which R¹ and R² are attached has (R) stereochemistry.

Within the above preferred and more preferred groups, an even more preferred group of compounds is where either:

(i) R²⁰ and R²¹ are independently hydrogen, alkyl, acyl, aralkyl, aralkenyl or heteroalkenyl;

(ii) R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a heterocycloamino group, more preferably where R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a piperidino or piperazino ring where:

the piperidino ring is optionally substituted at the 4-position by aryl, heteroaryl, acyl, --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), --OR (where R is aryl or heteroaryl), or --S(O)_(n) R (where n is an integer from 0-2 and R is aryl or heteroaryl), more preferably phenyl, phenoxy, 4-(imidazol-1-yl)phenoxy, 5-chloropyridin-2-yloxy, 4-chlorophenoxy, 4-fluorophenoxy, 4-chlorobenzoyl, 4-cyanobenzoyl, 4-methylbenzoyl, 4-chlorophenylsulfonyl, phenylthio, pyridin-4-ylthio, pyridin-2-ylthio, benzoxazol-2-yl, benzothiazol-2-ylthio, 5-phenylthiazol-2-yl, 5-fluoroindol-3-yl, 6-chloroindol-3-yl, 5-phenylimidazol-2-yl, benzimidazol-2-yl, 4-methylphenylthio, 4-chlorophenylthio, 4-cyanophenyl, 4-fluorophenyl, 4-fluorobenzoyl, 4-fluorophenylaminocarbonyl, 5-chloroindol-3-yl, 5-chlorobenzotriazol-1-yl, 6-methylindol-3-yl, 5-fluoroindol-3-ylcarbonyl, 6-fluoroindol-3-yl, 4,5,6,7-tetrafluoroindol-3-yl, 4-chloroindol-3-yl, 7-methylindol-3-yl, 5-cyanoindol-3-yl, 6-cyanoindol-3-yl, benzothiophen-2-yl, benzothiophen-3-yl, quinolin-3-yl, 5-chlorobenzimidazol-1-yl, pyridin-2yloxy, 6-chloropyridin-2-yloxy, naphth-1-yl, naphth-2-yl, 1,2,3,4-tetrahydro-β-carboline, 7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, 8-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, 7-fluoro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, or 8-fluoro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, most preferably 4-chlorophenoxy, 4-fluorophenoxy, 4-fluorophenyl, 5-chloropyridin-2-yloxy, 6-chloropyridin-2-yloxy, pyridin-2-yloxy, phenoxy, phenylthio, pyridin-4-ylthio, 4-chlorobenzoyl, 5-fluoroindol-3-yl, 4,5,6,7-tetrafluoroindol-3-yl, 6-methylindol-3-yl, 5-chloroindol-3-yl, 5-cyanoindol-3-yl, 5-chlorobenzotriazol-1-yl, 1,2,3,4-tetrahydro-β-carboline, or 6-chloroindol-3-yl; and

the piperazino ring is optionally substituted at the 4-position by aryl, heteroaryl, --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), or --SO₂ aryl, more preferably 4-chlorophenyl, 5-chloropyridin-2-yl, 4-benzyloxyphenyl, 4-(pyridin-4-yl)methyloxyphenyl, 2-phenylbenzoxazol-5-yl, pyridin-4-yl, 5-trifluoromethyl-pyridin-2-yl, 4-cyanophenyl, 5-nitropyridin-2-yl, 5-bromopyridin-2-yl, 4-biphenylaminocarbonyl, 4-phenoxyphenyl-aminocarbonyl, 4-benzyloxyphenylaminocarbonyl, or 4-chlorophenylaminocarbonyl, most preferably 4-chlorophenyl, 4-benzyloxyphenyl, 5-chloropyridin-2-yl, 4-cyanophenyl, 4-chlorophenylaminocarbonyl, or 2-phenylbenzoxazol-5-yl; or

(iii) R²⁰ and R²¹ together with the nitrogen atom to which they are attached form 1,2,3,6-tetrahydropyridine ring which is substituted at the 4-position by an aryl or heteroaryl ring, preferably phenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-fluoro-3-methylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methoxyphenyl, 3-chloro-4-fluorophenyl, 5-chloroindol-3-yl, 5-fluoroindol-3-yl or 3,4-difluorophenyl, most preferably 4-chlorophenyl, 4-fluorophenyl, 4-fluoro-3-methylphenyl, or 3-chloro-4-fluorophenyl.

(II) Carboxylic Acids

Compounds of formula (I) where R¹⁰ is --OH.

Within this group of compounds a preferred group is that wherein:

R¹ is hydrogen, alkyl, aryl, aralkyl, or heteroalkyl, preferably alkyl, aryl, or heteroalkyl, more preferably hydrogen, 2-propyl, tert-butyl, 1-hydroxyethyl, tert-butoxymethyl, 2,2-dimethylpropyl, 2-methylpropyl, 1-methylpropyl, propyl, benzyl, phenyl, 4-fluorophenyl, cyclohexyl, (1-methyl-1-methylthio)ethyl, phenythiomethyl, benzylthiomethyl, thiophen-2-ylthiomethyl, pyridin-2-ylthiomethyl, 4-(benzyloxycarbonylamino)butyl, or benzyloxymethyl, most preferably hydrogen, methyl, or 2-propyl;

R² is hydrogen; and

R³ is hydrogen, alkyl, aralkyl, heteroaralkyl, or heteroalkyl, preferably hydrogen, benzyl, N,N-dimethylaminoethyl, or pyridin-3-ylmethyl, most preferably hydrogen, benzyl or pyridin-3-ylmethyl, provided that R¹, R² and R³ are not all hydrogen.

Within this group, particularly preferred compounds are those where the spatial arrangement of the groups at the carbon atom to which R¹ and R² are attached is as shown in FIG. 1 below. ##STR6##

Another preferred group of compounds is that wherein R¹ and R² together with the carbon atoms to which they are attached form a carbocycle or heterocycle, preferably a carbocycle with a ring size between 3 to 6 carbon atoms, more preferably 5 or 6 carbon atoms, or a heterocycle of 6 ring atoms containing a single N, O, or S atom with the carbon to which R¹ and R² are attached being in the 4-position of the heterocycle, most preferably cyclopentyl, cyclohexyl, or piperidino ring where the nitrogen in the piperidino ring is optionally substituted with acyl, --SO₂ R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), or --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl); and

R³ is as described above.

Yet another preferred group of compounds is that wherein R³ and R¹ together with the atoms to which they are attached form a heterocycloamino group, preferably a heterocycloamino group with a ring size of 6 ring atoms and optionally containing a second heteroatom selected from the group consisting of N, O, or S(O)_(n) (where n is an integer from 0-2), preferably at the 4-position with the nitrogen atom to which R³ is attached being in the 1-position of the heterocycloamino group. Representative heterocycloamino groups formed by R³ and R¹ include, but are not limited to, piperidino, morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, 2,2-dimethylthiomorpholino, or piperazino wherein the nitrogen at the 4-position of the piperazino ring is optionally substituted with alkyl, haloalkyl, cycloalkylalkyl, acyl, -(alkylene)-COOR^(a) (where R^(a) is alkyl), --SO₂ R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), --CONR'R", or -(alkylene)-CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), preferably acyl, haloalkyl, --SO₂ R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), or --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), more preferably acetyl, formyl, 2,2,2-trifluoroethyl, aminocarbonyl, N,N-dimethylaminocarbonyl, 2,4-difluorophenylaminocarbonyl, N,N-dimethylaminosulfonyl, bis(N,N-dimethylaminophosphoryl), morpholin-4-ylcarbonyl, morpholin-4-ylsulfonyl, or 1,4-pyrazin-2-ylcarbonyl.

Within this group, particularly preferred compounds are those where the spatial arrangement of the groups at the carbon atom to which R¹ and R² are attached has (R) stereochemistry.

Within the above preferred groups, a more preferred group of compounds is where either:

(i) R²⁰ is hydrogen or alkyl, preferably hydrogen or methyl; most preferably methyl; and

R²¹ is aryl, aralkyl, or heteroaralkyl, preferably benzyl, 4-biphenylmethyl, 3-(4-biphenyl)propyl or 2-phenylethyl, most preferably benzyl or 4-biphenylmethyl;

(ii) R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a heterocycloamino group substituted with an aryl or heteroaryl ring, more preferably where R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a piperidino or piperazino ring substituted at the 4-position by aryl or heteroaryl, most preferably where:

the piperidino ring is substituted by 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-fluoro-3-methylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methoxyphenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 4-(pyridin-4-ylmethyloxy)phenyl, 4-(pyridin-3-ylmethyloxy)phenyl, 5-chloropyridin-2-yl, 5-chloropyridin-2-yloxy, 6-fluorobenzisothiazol-3-yl, 6-chloroindol-3-yl, 5-chloroindol-1-yl, 5-fluoroindol-3-yl, 4,5,6,7-tetrafluoroindol-3-yl, or 6-fluoroindol-3-yl, most preferably 4-chlorophenyl, 4-fluorophenyl, 5-chloropyridin-2-yloxy, 6-fluorobenzisothiazol-3-yl, 4-(pyridin-4-ylmethyloxy)phenyl, or 6-fluorobenzisothiazol-3-yl; and

the piperazino is substituted by 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-fluoro-3-methylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methoxyphenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 4-(pyridin-4-ylmethyloxy)phenyl, 4-(pyridin-3-yl -methyloxy)phenyl, 5-chloropyridin-2-yl, 6-fluorobenzisothiazol-3-yl, 6-chloroindol-3-yl, 5-chloroindol-1-yl, 5-fluoroindol-3-yl, 4,5,6,7-tetrafluoroindol-3-yl, or 6-fluoroindol-3-yl, most preferably 4-chlorophenyl, 4-fluorophenyl, 6-fluorobenzisothiazol-3-yl, 4-(pyridin-4-ylmethyloxy)phenyl, or 6-fluorobenzisothiazol-3-yl;

(iii) R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a 1,2,3,6-tetrahydropyridine ring which is substituted at the 4-position by aryl or heteroaryl, more preferably 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-methylphenyl, 4-fluoro-3-methylphenyl, 4-chloro-3-trifluoromethylphenyl, 4-methoxyphenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl, 4-(pyridin-4-ylmethyloxy)phenyl, 4-(pyridin-3-ylmethyloxy)phenyl, 5-chloropyridin-2-yl, 6-fluorobenzisothiazol-3-yl, 6-chloroindol-3-yl, 5-chloroindol-1-yl, or 6-fluoroindol-3-yl, most preferably 4-chlorophenyl, 4-fluorophenyl, or 4-fluoro-3-methylphenyl; or

(iv) R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a heterocycloamino group that is fused to a cycloalkyl, aryl or heteroaryl ring.

Exemplary particularly preferred compounds are:

N-hydroxy-2-(R)-{[4-(4-chlorophenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide.

N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide.

N-hydroxy-2-(R)-{[4-(4-fluorophenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide.

N-hydroxy-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.

N-hydroxy-2-(R)-{[4-(4-benzyloxyphenyl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.

N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.

N-hydroxy-2-(R)-{[4-(2-phenylbenzoxazol-5-yl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.

N-hydroxy-1-[4-(phenoxy)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide

N-hydroxy-1-[4-(phenylthio)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.

N-hydroxy-1-[4-(pyridin-4-ylthio)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide.

N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide.

N-hydroxy-1-[4-(6-chloroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.

N-hydroxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.

N-hydroxy-4-acetyl-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(RS)-carboxamide.

N-hydroxy-2-(R)-3-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylvaleramide.

N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-4-methylvaleramide.

N-hydroxy-2-(R)-3-(S)-{[4-(chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylvaleramide.

N-hydroxy-2-(R)-{[4-(6-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-4,4-dimethylvaleramide.

N-hydroxy-1-[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.

N-hydroxy-1-[4-(5-chloroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.

N-hydroxy-1-[4-(5-chlorobenzotriazol-1-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.

N-hydroxy4-acetyl-1-[4-(6-methylindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(RS)-carboxamide.

N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-4-formylpiperazine-2-(RS)-carboxamide.

N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}valeramide.

N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-4-methylvaleramide.

N-hydroxy-2-(R)-{[4-(4-cyanophenyl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.

N-hydroxy-2-(R)-{[4-(4-chlorophenylaminocarbonyl)piperazine-1-sulfonyl]amino}-3-methylbutyramide.

N-hydroxy-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}valeramide.

N-hydroxy-1-[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide.

N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-4-(N,N-dimethylaminocarbonyl)piperazine-2-(R)-carboxamide.

N-hydroxy4-(N,N-dimethylaminocarbonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-4-(N,N-dimethylaminosulfonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-4-(N,N-dimethylaminosulfonyl)piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-4-(1,4-pyrazin-2-ylcarbonyl)piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]-4-(morpholin-4-yl-carbonyl)piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide.

N-hydroxy-2-(R)-(4-fluorophenyl)-2-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}acetamide.

N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperidine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(2,2,2-trifluoroethyl)piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]-4-(2,2,2-trifluoroethyl)piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]-4-(morpholin-4-ylcarbonyl)piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]-4-(morpholin-4-ylsulfonyl)piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(morpholin-4-ylsulfonyl)piperazine-2-(R)-carboxamide.

N-hydroxy-4-(N,N-dimethylaminosulfonyl)-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-4-(N,N-dimethylaminosulfonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-4-[bis(N,N-dimethylaminophosphoryl)]-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-4-[bis(N,N-dimethylaminophosphoryl)]-1-[4-(4-fluorophenyl)-piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-4-(2,4-difluorophenylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropiperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-3-oxo-piperazine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-4(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-3-oxo-piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-5-hydroxy-1,2,3,6-tetrahydropiperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-methylbutyramide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3,3-dimethylbutyramide.

N-hydroxy-1-[1,2,3,4-tetrahydro-beta-carboline-2-sulfonyl]piperidine-2-(R)-carboxamide.

N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[7-fluoro-1,2,3,4-tetrahydro-beta-carboline-2-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-4-aminocarbonyl-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]-4-formylpiperazine-2-(R)-carboxamide.

N-hydroxy-4-acetyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-4-tert-butylaminocarbonyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-fluoro-3-methylphenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperidine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(N,N-dimethylaminocarbonyl)piperazine-2-(R)-carboxamide.

N-hydroxy-N-methyl-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]-4-(2,2,2-trifluoroethyl)piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(morpholin-4-ylcarbonyl)piperazine-2-(R)-carboxamide.

N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]4-(tert-butoxycarbonyl)piperazine-2-(R)-carboxamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-2-cyclohexylacetamide.

N-hydroxy-2-(R)-{(pyridin-3-ylmethyl)-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-2-(4-fluorophenyl)acetamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-(S)-hydroxybutyramide.

N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(S)-hydroxypiperidine-2-(R)-carboxamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-2-(4-hydroxyphenyl)acetamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)piperidine-1-sulfonyl]amino}-2-(4-hydroxyphenyl)acetamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-4-methylvaleramide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-phenylpropionamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-(4-hydroxyphenyl)propionamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-(S)-methylvaleramide.

N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(N-methylaminocarbonyl)piperazine-2-(R)-carboxamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}valeramide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-4-pentenamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-(thien-2-yl)propionamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-4-methylthiobutyramide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-tert-butoxypropionamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-benzyloxypropionamide.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-(R)-methylvaleramide.

2-[benzyl-(benzylmethylaminosulfonyl)amino]acetic acid.

2-(R)-{benzyl-[(4-biphenylmethyl)methylaminosulfonyl)]amino]-3-methylbutyric acid.

2-(R)-{[4-(4-chlorophenyl)piperidine-1-sulfonyl]amino}propionic acid.

2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyric acid.

1-[4-(6-fluorobenzisothiazol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid.

1-[4-(6-chloroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid.

1-[4-(4-chlorophenyl)piperidine-1-sulfonyl]-4-(N,N-dimethylaminocarbonyl)piperazine-2-(R)-carboxylic acid.

4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxylic acid.

2-(R)-{[4-(4-chlorophenyl)piperazino-1-sulfonyl]amino}propionic acid.

2-(R)-{[4-(4-fluorophenyl)piperazino-1-sulfonyl]amino}acetic acid.

2-(R)-{[4-(4-chlorophenyl)piperazino-1-sulfonyl]amino}acetic acid.

2-(R)-{[4-(pyridin-4-ylmethyloxyphenyl)piperazino-1-sulfonyl]amino}-3-methylbutyric acid.

6-benzyloxycarbonylamino-2-(R)-{[4-(5-chlorophenyl)piperazino-1-sulfonyl]amino}hexanoic acid.

2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-3-methylbutyric acid.

1-[4-(4-fluoro-3-methylphenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperidine-2-(R)-carboxylic acid.

1-[4-(3-chloro-4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperidine-2-(R)-carboxylic acid.

1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(N,N-dimethylaminocarbonyl)piperazine-2-(R)-carboxylic acid.

1-[4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(N,N-dimethylaminosulfonyl)piperazine-2-(R)-carboxylic acid.

N-hydroxy-1-[6-fluoro-1,2,3,4-tetrahydro-beta-carboline-2-sulfonyl]piperidine-2-(R)-carboxylic acid.

N-hydroxy-2-(R)-{[1,2,3,4-tetrahydro-beta-carboline-2-sulfonyl]amino}propionic acid.

N-hydroxy-2-(R)-{(pyridin-2-ylmethyl)-[1,2,3,4-tetrahydro-beta-carboline-2-sulfonyl]amino}propionic acid.

N-hydroxy-2-(R)-{[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]amino}-4-methylvaleric acid.

General Synthetic Scheme

Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.

The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., U.S.A.), Bachem (Torrance, Calif., U.S.A.), Ernka-Chemie, or Sigma (St. Louis, Mo., U.S.A.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.

The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

In general, compounds of formula (I) can be prepared from alkyl 2-[(aminosulfonyl)amino]acetates of formula Ia.

Preparation of Compounds of Formula Ia

Schemes A, B, and C describe alternative methods to generate the compounds of formula Ia.

A compound of formula Ia where R³ can optionally be hydrogen is prepared from an alpha-amino acetate 1 as shown in Scheme A. ##STR7##

In Step 1, a 2-[(chlorosulfonyl)amino]acetate of formula 2 is prepared, either:

(a) by reacting an alpha-amino acetate 1 (where R is alkyl, preferably methyl, ethyl, or tert-butyl and R³ is as defined in the Summary of the Invention) with sulfuryl chloride in an aprotic organic solvent (e.g., dichloromethane, tetrahydrofuran, dioxane, acetonitrile, and the like). The reaction may be carried out with or without the presence of an organic base (e.g., triethylamine or pyridine). If an organic base is used, the reaction is carried out at temperatures ranging from -78° C. to 25° C., otherwise it is carried out between 25° C. to 80° C.; or

(b) by reacting chlorosulfonic acid with an excess amount of compound 1, or with an equimolar amount of compound 1 in the presence of a non-nucleophilic organic base to give a sulfamic acid intermediate. The reaction is carried out in chlorinated hydrocarbons (e.g., dichloromethane, chloroform, and the like) at 0° C. to 30° C. The sulfamic acid intermediate is then converted to a 2-[(chlorosulfonyl)amino]acetate of formula 2 by reacting it with a suitable chlorinating agent (e.g., phosphorus pentachloride, thionyl chloride, phosphorus oxychloride, preferably phosphorus pentachloride, and the like). The reaction proceeds upon heating at temperatures ranging from 70° C. to 110° C. Suitable solvents for the reaction are aromatic hydrocarbons such as benzene, toluene, and the like.

In general, compounds of formula I are commercially available or they can be prepared by methods well known in the field of organic chemistry. For example, esters of natural and unnatural amino acids such as alanine, valine, pipecolinic acid, etc., are readily available from Aldrich.

Compounds of formula 1 where R¹ and R³ together form a morpholino ring can be prepared by following the procedures described in Brown, G. R., Foubister, A. J., Wright, B., J. Chem. Soc. Perk. Trans. I, 2577, (1985) and Kogami, Y., Okawa, K. Bull. Chem. Soc. Jpn., 60, 2963, (1987). Alpha-thiomethyl amino acids can be prepared by following the procedures described in Arnold, L. D., Kalantar, T. H., Vederas, J. C. J. Am. Chem. Soc., 107, 7108, (1985).

Compounds of formula 1 where R³ is not hydrogen can be prepared under reductive amination reaction conditions by reacting a corresponding alpha-amino acetate 1 where R³ is hydrogen with an aldehyde or ketone in the presence of a suitable reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, and the like) and an organic acid (e.g., glacial acetic acid, trifluoroacetic acid, and the like) at ambient temperature. Suitable solvents for the reaction are halogenated hydrocarbons (e.g., 1,2-dichloroethane, chloroform, and the like).

In Step 2, a compound of formula Ia is prepared by reacting a compound of formula 2 either with an excess amount of an amine of formula 3 or with an equimolar amount of the amine 3 in the presence of a non-nucleophilic organic base (e.g., triethylamine or pyridine, preferably pyridine). The reaction is carried out at temperatures ranging from -78° C. to 30° C., preferably at 0° C. Suitable solvents for the reaction are dichloromethane, diethyl ether, tetrahydrofuran, and the like. Alternatively, a compound of formula Ia is prepared by reacting a compound of formula 2 with an excess of an amine of formula 3 or its corresponding ammonium salt in the presence of an excess of a water soluble base (e.g., sodium carbonate, sodium bicarbonate, or sodium hydroxide). Suitable solvents for the reaction are aqueous solvent mixture such as dioxane/water or tetrahydrofuran/water. The reaction is carried out at temperatures ranging from 0° C. to 100° C., preferably at RT.

Generally, amines of formula 3 are commercially available e.g., benzylamine, N-ethylmethylamine, 4-chlorophenylpiperazine, 4-phenoxypiperidine, 4-(4-methylphenyl)piperazine, 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine, etc., are commercially available. Others can be prepared from starting materials such as 1-tert-butoxycarbonyl-4-hydroxypiperidine, 1-tert-butoxycarbonylisonipecotic acid, 1-tert-butoxycarbonylpiperazine, 1-benzyloxycarbonyl-4-piperidone, piperazine etc., by following the literature procedures such as those listed below.

For general piperazine synthesis and arylation, see, Saari, W. S., Halczenko, W., King, S. W., Huff, J. R., Guare, J. P., Hunt, C. A., Randall, W. C., Anderson, P. S., Lott, V. J., Taylor, D. A., Clineschmidt, B. U. J. Med. Chem., 26, 1696, (1983); Kuipers, W., Wijngaarden, I., Knose, C. G., Amstel, M., Tulp, M. I., Zerman, A. J. Med. Chem., 38, 1942, (1995); Verderame, M. J. Med. Chem., 15, 693, (1972); and Herrin, T. R.; Paullik, J. M., Schuber, E. V., Geiszler, A. O. J. Med. Chem., 18, 1216, (1975).

For indole-substituted piperidine analogs, see, Guillaume, J., Dumont, C., Laurent, J., Nedelec, L. Eur. J. Med. Chem., 22, 33, (1987); Perregaard, J., Arnt, J., Bogeso, K. P., Hyttel, J., Sanchez, C. J. Med. Chem., 35, 1092, (1992); Andersen, K., Perregaard, J., Arnt, J., Nielsen, J. B., Begtrup, M. J. Med. Chem. 35, 4823, (1992), Bergman, J., Venemalm, L. Tetrahedron, 46, 6061, (1990); and Sasakura, K., Adachi, M., Sugasawa, T. Synth. Comm., 18(3), 265 (1988).

For benzotriazole and benzisoxazole-substituted piperidine analogs, see, Sato, M., Arimoto, M., Ueno, K. J. Med. Chem., 21, 1116, (1978); 4-benzoxazole-2-ylpiperidines Nestor, J. J. Jr., Homer, B. L., Ho, T. L. Jones, G. H., McRae, G. I., Vickery, B. H. J. Med. Chem., 27, 320 (1984); and Strupczewski, J. T., Allen, R. C., Gardner, B. A., Schmid, B. L., Stache, U., Glamkowski, E. J., Jones, M. C., Ellis, D. B., Huger, F. P., Dunn, R.W. J. Med. Chem., 28, 761, (1985) respectively.

For 4-(benzisothiazol-3-yl)piperidines and 4-(indazol-3-yl)piperidines, see, Fink, D. M., Strupczewski, J. T. Tetrahedron Lett., 6525, (1993) and Strupczewski, J. T. European Patent 0135781, 1989.

For benzimidazole-substituted and related piperidine and piperazine analogs, see, Henning, R., Lattrell, R., Gerhards, H. J., Leven, M. J. Med. Chem., 30, 814-9, (1987); Nomoto, Y., Obase, H., Takai, H., Hirata, T., Teranishi, M., Nakamura, J., Kubo, K. Chem. Pharm. Bull., 38(6), 1591, (1990); Nestor, J. J., Homer, B. L., Ho, T. L., Jones, G. H., McRae, G. I., Vickery, B. H. J. Med. Chem., 27, 320, (1984); Chen, J. J., Zhang, Y., Hammond, S., Dewdney, N., Ho, T., Lin, X., Browner, M. F., Castelhano, A. Tetrahedron Lett., 1601 (1996) and Von Geldern, T. W., Hutchins, C., Kester, J. A., Wu-Wong, J. R., Chiou, W., Dixon, D. B., Opgenorth, T. J., J. Med. Chem., 39, 957, (1996).

For 1,2,3,4-tetrahydro γ- or β-carbolines, see, Harbert, C. A., Plattner, J. J., Welch, W. M. J. Med. Chem., 23, 635 (1980) and Still, I. W. J., Strautmanis, J. R. Can. J. Chem., 68, 1408, (1990) and Ho, B. T ., McIsaac, W. M., Tansey, L. W. J. Pharm. Sci., 58, 998, (1969).

For 4-arylthiazol-2-ylpiperidines and 4-arylimidazol-2-ylpiperidines, see, Von Geldern, T. W., Hutchins, C., Kester, J. A., Wu-Wong, J. R., Chiou, W., Dixon, D. B., Opgenorth, T. J. J. Med. Chem., 39, 957 (1996).

For hydroxy-substituted pipecolic acid, see, Gillard, J., Abraham, A., Anderson, P. C., Beaulieu, P. L., Bogri, T., Bousquet, Y., Grenier, L., Guse, I., Lavallee, P. J. Org. Chem., 61, 2226, (1996).

For 4-substituted 1,2,3,6-tetrahydropyridine analogs, see, Wustrow, D. J., Wise, L. D. Synthesis, 993, (1991); Perregaard, J., Moltzen, E. K., Meier, E., Sanchez, C. J. Med. Chem., 38, 1998, (1995); and Bolttcher, H., Barnickel, G., Hausbery, H., Hasse, A. F., Seyfled, C. A., Eiermann, V. J. Med. Chem., 35, 4020 (1992).

Alternatively, compound Ia can be prepared in one step as shown in Step 1,2 (alt.) by reacting the alpha-amino acetate 1 with a sulfonyl chloride 4, utilizing the reaction conditions described in Step 2 above.

The sulfamoyl chloride 4 can be prepared from the corresponding amine 3 by proceeding as described in Step 1 above. It should be understood that if 3 is a heterocycloamino group substituted with an electron rich heteroaromatic ring, then it may become necessary, in some cases, to deactivate the heteroaromatic ring with a deactivating protecting group before carrying out the sulfonylating reaction. This is done to prevent sulfonylation from occurring on the heteroaromatic ring. For example, where 3 is a 4-(indol-3-yl)piperidino group, the indole nitrogen has to be protected by a deactivating protecting group (such as trimethylsilylethanesulfonyl, acetyl, and the like) prior to converting it to the sulfamoyl chloride.

It will be recognized by one skilled in the art that a compound of formula Ia can be converted to a new compound of formula Ia using methods that do not affect the ester and sulfamide groups. For example, a compound of formula Ia where R³ is hydrogen, can be converted to a corresponding compound of formula Ia where R³ is not hydrogen, if required, either:

(a) by reacting compound Ia where R³ is hydrogen with an alkylating agent R³ X, (where X is a leaving group such as chloro, bromo, mesylate, triflate, and the like under alkylating conditions) in the presence of a base (e.g., sodium carbonate, potassium carbonate, sodium hydride and the like) and at reaction temperatures ranging from 0° C. to 30° C. Suitable solvents for the reaction are THF, dioxane, N,N-dimethylformamide and the like; or

(b) by reacting compound Ia with a hydroxy compound of formula R³ OH in the presence of a trialkylphosphine or a triaryl phosphine, preferably triphenylphosphine, and a dialkyl azodicarboxylate such as diethyl or diisopropyl azodicarboxylate.

Additionally, a compound of formula Ia where R²⁰ and R²¹ along with the nitrogen atom to which they are attached form a 4-piperidone ring can be reacted with trimethylsilyl trifluoromethanesulfonate and a nucleophile, such as a 3-unsubstituted pyrrole or indole, to give a compound of formula Ia where R²⁰ and R²¹ along with the nitrogen atom to which they are attached is a 4-substituted-1,2,3,6-tetrahydropyridine ring, a 4,4-disubstituted-piperidino ring, or a 4-hydroxy-4-substituted piperidino ring depending on the reactivity of the nucleophile used. The reaction is carried out in a non-hydroxylic solvent, preferably methylene chloride or acetonitrile, at reaction temperatures ranging from -30° C. to 30° C.

A compound of formula Ia where R³ is not hydrogen and R²¹ may optionally be hydrogen, is prepared from an alpha-amino acetate 1 as shown in Scheme B. ##STR8##

In Step 1, a compound of formula Ia where R³ is not hydrogen and R²¹ is hydrogen is prepared by proceeding as described in Step 1,2 (alt.) of Scheme A, but substituting a sulfamoyl chloride of formula 5 for a compound of formula 4.

The sulfamoyl chloride of formula 5 is prepared from a corresponding isocyanate, utilizing the reaction conditions such as those described in Kloek, J. A. and Leschinsky, K. L., J. Org. Chem, 46, 4028, (1976). The required isocyanate is commercially available or can be prepared by methods known to one skilled in the art.

In Step 2 (optional), a compound Ia where R²¹ is hydrogen can be converted to a corresponding compound of formula Ia where R²¹ is not hydrogen, by proceeding as described in Step 3 (optional) of Scheme A.

A compound of formula Ia where R² is hydrogen and R³ may optionally be hydrogen is prepared from an alpha-hydroxyacetate 8 or its derivative 6 as shown in Scheme C. ##STR9##

In Step 1, a 2-[(aminosulfonyl)amino]acetate of formula Ia where R² is hydrogen is prepared by reacting an acetate derivative of formula 6 where L is a leaving group under alkylating conditions (e.g., para-toluenesulfonate, triflate, and the like) with a mixed sulfamide (R³ is hydrogen) or a cyclic sulfamide (R³ and R²⁰ or R²¹ form an alkylene chain) of formula 7 at reaction temperatures ranging from -78° C. to -30° C. The reaction is carried out in the presence of a base (e.g., sodium hydride, potassium tert-butoxide, and the like) in a suitable polar aprotic organic solvent such as diethyl ether, tetrahydrofuran, and the like.

The mixed sulfamide 7 is prepared by heating the commercially available sulfamide (NH₂ SO₂ NH₂) with an amine of formula 3 (where R²⁰ and R²¹ are as defined in the Summary of the Invention except hydrogen) in an aqueous medium. The cyclic sulfamide is prepared by reacting an alkylene diamine with sulfuryl chloride in aprotic organic solvent such as tetrahydrofuran.

Alternatively, compound Ia can be prepared in two steps as shown in Step 1 (alternative), by first preparing an N-tert-butoxycarbonyl-2-[(aminosulfonyl)amino]acetate of formula 10 which is then converted to a compound of formula Ia by removal of the N-protecting group. If compound 10 is the tert-butyl ester (i.e. R=tert-butyl), it is hydrolyzed under the reaction conditions utilized for the removal of the tert-butoxycarbonyl group thereby giving compound of formula (I) (where R¹⁰ =--OH) instead of compound of formula Ia. Compound 10 is prepared by reacting a 2-hydroxyacetate of formula 8 with an N-Boc protected sulfamide of formula 9 under reaction conditions such as those described in Step 3, method (b) of Scheme A.

Compound 9 is prepared by protecting the amino group in a corresponding sulfamide of formula 7 with di-tert-butyl dicarbonate.

The compound Ia where R³ is hydrogen can be converted to a corresponding compound of formula Ia where R³ is not hydrogen, by proceeding as described in Step 3 (optional) of Scheme A.

Preparation of Compounds of Formula (I)

Schemes D and E describe methods to prepare compounds of formula (I) from compounds of formula Ia.

Compounds of formula (I) where R¹⁰ is hydroxy can be prepared by the methods shown in Scheme D. ##STR10##

In Step 1, a compound of formula (I) where R¹⁰ is hydroxy is prepared from a corresponding compound of formula Ia by hydrolysis of the ester group --OR. In general, the hydrolysis is carried out in the presence of an aqueous base (e.g., sodium hydroxide, lithium hydroxide, and the like) in an alcoholic organic solvent such as methanol, ethanol, and the like. However, when compound Ia is optically active and the carbon atom to which R¹ and R² are attached is a chiral center and either R¹ or R² is hydrogen, the hydrolysis is carried out with aqueous lithium hydroxide in order to prevent racemization from occurring at this chiral center. The hydrolysis reaction proceeds either at ambient temperature or upon heating. Furthermore, if compound Ia is an acid labile ester, such as a tert-butyl ester, then the hydrolysis can be carried out in the presence of an acid (e.g., para-toluenesulfonic acid, trifluoroacetic acid, dry hydrochloric acid, and the like) and in an inert organic solvent such as methylene chloride, benzene, and the like.

Alternatively, compound (I) where R¹⁰ is hydroxy may be prepared directly from the alpha-amino acid 11 (Z=hydrogen) or its corresponding salt (Z=sodium, ammonium, and the like) as shown in Step 1 (alt.). The acid 11 or its salt is first solubilized with a suitable solubilizing agent such as trimethylsilylcyanide and then reacted with a sulfamoyl chloride of formula 4.

Compounds of formula (I) where R¹⁰ is an --NR¹¹ OR¹² group where R¹¹ and R¹² are as defined in the Summary of the Invention are prepared by the methods shown in Scheme E. ##STR11##

Method (a)

In Step 1, a compound of formula (I) where R¹¹ and R¹² are as defined in the Summary of the Invention except R¹² is not hydrogen is prepared by reacting a corresponding acid compound of formula (I) (where R¹⁰ =--OH) with an N,O-disubstituted hydroxylamine (e.g., N,O-dimethylhydroxylamine, and the like) or an O-substituted hydroxylamine (e.g., O-benzylhydroxylamine, O-tert-butylhydroxylamine, and the like). The reaction is carried out in the presence of a coupling agent (e.g., N,N-dicyclohexylcarbodiimide, N-ethyl-N'-(3-dimethylamino-propyl)carbodiimide, and the like), an organic base (e.g., dimethylamino-pyridine, triethylamine, pyridine, N-methylmorpholine, and the like) and optionally hydroxybenzotriazole. The reaction is carried out at temperatures ranging from 0° C. to 40° C., preferably ambient temperature. Suitable solvents for the reaction are methylene chloride, dichloroethane, DMF, and the like.

In Step 2, (optional), a compound of formula (I) where R¹² is hydrogen is prepared from the corresponding compound of formula (I) where R¹² is not hydrogen by removal of the R¹² group. The reaction conditions utilized depend on the nature of the R¹² group e.g., if R¹² is tert-butyl, then the reaction is carried out in an inert solvent such as dichloromethane, in the presence of an acid (e.g., dry hydrogen chloride, trifluoroacetic acid, and the like) at 0° C. to 25° C. If R¹² is benzyl, then hydrogenolysis conditions utilizing a metal catalyst such as palladium in an inert solvent such as ethyl acetate or tetrahydrofuran are required.

Alternatively, a compound of formula (I) where R¹¹ and R¹² are both hydrogen can be prepared by reacting a corresponding acid compound of formula (I) (where R¹⁰ =--OH) with an O-substituted hydroxylamine such as O-tert-butyldimethylsilylhydroxylamine, followed by treatment with an acid as described above. It will be recognized by one of ordinary skill in the art that compounds of formula (I) where either R¹¹ or R¹² is not hydrogen can be prepared by other procedures well known in the art. For example, a compound of formula (I) where R¹¹ is not hydrogen can be prepared by alkylating the corresponding compound of formula (I) where R¹¹ is hydrogen under the reaction conditions described in Scheme A above.

Method (b)

A compound of formula (I) where R¹¹ is as defined in the Summary of the Invention and R¹² is not hydrogen can be prepared by reacting an O-substituted or an N,O-disubstituted-N-hydroxy-2-amino acetamide of formula 13 with a sulfamoyl chloride 4 under the reaction conditions described in Step 1, 2 (alt.) of Scheme A. Compound 13 is prepared by proceeding as described in method (a) (above) but substituting a suitable orthogonally N-protected amino acid (e.g., N-CBZ-glycine or N-BOC-alpha amino isobutyric acid) for an acid of formula (I), followed by removal of the alpha amino protecting group.

Method (c)

A compound of formula (I) where R¹⁰ is --NR¹¹ OH (where R¹¹ is as defined in the Summary of the Invention) can also be prepared by reacting an acyl derivative of formula 14 where Y is a leaving group under acylating conditions (e.g., chloro, succinimido, and the like) with a suitably protected hydroxylamine (e.g., N,O-bis-trimethylsilylhydroxylamine, N-methylhydroxylamine), or an aqueous solution of hydroxylamine. The reaction is carried out at reaction temperatures ranging from -30° C. to 25° C. and in a suitable organic solvent such as methylene chloride, tetrahydrofuran, tert-butanol, and the like. When N,O-bis(trimethylsilyl)hydroxylamine is used, compound (I) where R¹⁰ is --NHOH is obtained directly since the trimethylsilyl group is cleaved during the acidic workup or upon the addition of methanol to the reaction mixture.

The acyl derivative 14 can be prepared from a corresponding compound of formula (I) where R¹⁰ is hydroxy by methods known to those of ordinary skill in the art. For example, compound 14 where Y is chloro can be prepared by reacting compound (I) where R¹⁰ is hydroxy with a chlorinating agent such as oxalyl chloride in a suitable organic solvent such as methylene chloride.

Method (d)

A compound of formula (I) where R¹⁰ is --NHOH can be prepared directly by reacting a methyl 2-[(aminosulfonyl)amino]acetate of formula Ia where at least one of R¹ and R² is hydrogen with hydroxylamine by the method described in Naruse et. al., J. Org. Chem., 59, 1358, (1994).

Utility, Testing, and Administration Utility

The hydroxamic acids and the carboxylic acids of formula (I) inhibit mammalian matrix metalloproteases (MMP's), such as the stromelysins, gelatinases, matrilysin, collagenases and human metalloelastase. The compounds and compositions containing them are therefore useful in the treatment of diseases associated with the MMP-induced excessive degradation of matrix and connective tissue within the mammal, such as arthritis (rheumatoid arthritis and osteoarthritis), multiple sclerosis, bone resorptive diseases (such as osteoporosis), the enhanced collagen destruction associated with diabetes, chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, corneal and gastric ulceration, ulceration of the skin, tumor invasion and metastasis, aneurysmal disease, and aberrant angiogenesis.

The compounds of formula (I) substantially inhibit the release of tumor necrosis factor (TNF) from cells, and are therefore useful for the treatment of conditions mediated by TNF, for example inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, cachexia and anorexia, acute infections, shock states, restenosis, graft versus host reactions and autoimmune disease. The compounds of the present invention may also inhibit the release of TNF without significant inhibition of the MMP's.

The compounds of this invention are therefore useful for treating a number of disease states, for example rheumatoid arthritis, multiple sclerosis, vascular disease, Type II diabetes, HIV, cachexia, psoriasis, allergy, hepatitis, inflammatory bowel disease, and cancer.

Testing

The ability of the compounds of formula (I) to inhibit matrix metalloprotease activity, such as the activity of collagenase-1, -2 and 3, stromelysin-1, gelatinases A and B, matrilysin and human metalloelastase may be demonstrated by a variety of in vitro assays known to those of ordinary skill in the art, such as the assay described in the MMP Enzymatic Assay described in FEBS, 296, 263, (1992) or modifications thereof as described in more detail in Example 32. It may also be assayed by the interleukin-1 stimulated cartilage explant assay and cartilage plug implantation assay as described in more detail in Examples 33 and 34.

The ability of the compounds of Formula (I) to inhibit the release of TNF may be assayed by an in vitro assay such as the TNF Monomac 6 assay and by in vivo assays such as the LPS induced TNF release assay and the TNF Receptor Shedding Immunoassay as described in more detail in Examples 35, 36, and 37.

Administration and Pharmaceutical Composition

In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors. The drug can be administered more than once a day, preferably once or twice a day.

Therapeutically effective amounts of compounds of formula I may range from approximately 0.05-35 mg per kilogram body weight of the recipient per day; preferably about 0.3-20 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 21 mg to 1.4 g per day.

In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

The compositions are comprised of in general, a compound of formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aide administration, and do not adversely affect the therapeutic benefit of the compound of formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of formula I based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of formula I are described in Example 30.

EXAMPLES

The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Abbreviations used in the examples are defined as follows: "HCl" for hydrochloric acid, "DMF" for dimethylformamide, "NaOH" for sodium hydroxide, "DMSO" for dimethylsulfoxide, "MgSO₄ " for magnesium sulfate, "RT" for room temperature, "PTLC" for preparatory thin layer chromatography, "SiO₂ " for silica gel, "EtOAc" for ethyl acetate, "APMA" for aminophenyl-mercuric acetate, "IL-1" for interleukin-1, and "RPMI" for Roswell Park Memorial Institute.

Synthetic Examples Example 1

Synthesis of ethyl 2-[benzyl-(morpholine-4-sulfonyl)amino]acetate ##STR12##

Step 1

A solution of triethylamine (2.0 ml, 14.4 mmol) and N-benzylglycine ethyl ester (2.25 ml, 12.0 mmol) in methylene chloride (5 ml) was added to a solution of sulfuryl chloride (0.96 ml, 12.0 mmol) in methylene chloride (30 ml) at -78° C. The reaction mixture was stirred at -78° C. for 4 h and then concentrated. Ether (75 ml) was added and the resulting precipitate was filtered. The organic layer was washed with 1M HCl and brine, dried over MgSO₄ and concentrated in vacuo to give ethyl 2-[benzyl-(chlorosulfonyl)amino]acetate as a colorless oil (69%).

Step 2

A solution of morpholine (1.05 ml, 12 mmol) and triethylamine (1.84 ml, 12 mmol) in methylene chloride (10 ml) was added to a solution of ethyl 2-[benzyl-(chlorosulfonyl)amino]acetate (2.3 g, 8.3 mmol), [prepared as described in Step 1 above], in methylene chloride (30 ml) at 0° C. The reaction mixture was slowly allowed to warm to RT and after 6 h 1M HCl was added. The product was extracted into methylene chloride, washed with brine, and dried over MgSO₄. The organics were removed in vacuo and the crude product was chromatographed (PTLC, SiO₂, 25% ethyl acetate/hexane) to give ethyl 2-[benzyl-(morpholine-4-sulfonyl)amino]acetate as a colorless oil (6%). Proceeding as described in Example 1 above, but substituting morpholine with:

4-methoxypiperidine;

benzylmethylamine; and

4-phenoxypiperidine, gave respectively,

ethyl 2-[benzyl-(4-methoxypiperidine-1-sulfonyl)amino]acetate (via methylation of the corresponding 4-hydroxypiperidine analog);

ethyl 2-[benzyl-(benzylmethylaminosulfonyl)amino]acetate;

ethyl 2-{[benzyl-(4-phenoxy)piperidine-1-sulfonyl]amino}acetate.

Example 2 Synthesis of methyl 2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyrate ##STR13##

Step 1

Chlorosulfonic acid (0.23 ml, 3.46 mmol) was added to a solution of (D)-valine methyl ester (1.36 g, 10.37 mmol) in methylene chloride (9 ml) at 0° C. and the reaction mixture was allowed to warm to RT. After 1.5 h, the solvent was removed in vacuo and the resulting solid was slurried in benzene (10 ml). Phosphorus pentachloride (0.72 g, 3.46 mmol) was added and the reaction mixture was heated at reflux. After 45 min., the solvent was evaporated and ether (75 ml) was added to the crude product. The solid was filtered and the filtrate was concentrated to give (D)-valinesulfamoyl chloride methyl ester as a colorless oil (87%).

Step 2

(D)-valinesulfamoyl chloride methyl ester (1.3 g, 5.6 mmol) [prepared as described in Step 1 above] was added to a solution of 4-(5-chloropyridin-2-yloxy)piperidine (1.2 g, 5.6 mmol) and triethylamine (3.21 ml, 22.5 mmol) in tetrahydrofuran (50 ml) at -78° C. After 2 h, the reaction mixture was diluted with ethyl acetate and then quenched with 0.5 M ammonium chloride. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo to give methyl 2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyrate as a pale yellow oil (75%). Proceeding as described above but substituting 4-(5-chloropyridin-2-yloxy)piperidine with:

4-(4-chlorophenoxy)piperidine;

4-(4-fluorophenoxy)piperidine;

4-(4-chlorophenyl)piperazine;

4-[(4-benzyloxy)phenyl]piperazine;

4-(5-chloropyridin-2-yl)piperazine;

4-[(2-phenylbenzoxazol-5-yl)piperazine;

4-[(4-chlorobenzylaminocarbonyl)methyl]piperidine, and

4-(4-phenylimidazol-2-yl)piperidine gave, respectively,

methyl 2-(R)-{[4-(4-chlorophenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyrate;

methyl 2-(R)-{[4-(4-fluorophenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyrate;

methyl 2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-methylbutyrate;

methyl 2-(R)-{[4-(4-benzyloxyphenyl]piperazine-1-sulfonyl]amino}-3-methylbutyrate;

methyl 2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-3-methylbutyrate;

methyl 2-(R)-{[4-[(2-phenylbenzoxazol-5-yl)piperazine-1-sulfonyl]amino}-3-methylbutyrate;

methyl 2-(R)-{[4-[(4-chlorobenzylaminocarbonyl)methyl]piperidine-1-sulfonyl]amino}-3-methylbutyrate; and

methyl 2-(R)-{[4-(4-phenylimidazol-2-yl)piperidine-1-sulfonyl]amino}-3-methylbutyrate.

Example 3 Synthesis of methyl 1[-4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylate ##STR14##

Step 1

Chlorosulfonic acid (3.0 ml, 44.0 mmol) was added dropwise to a solution of 4-(4-chlorophenyl)piperazine (7.12 g, 44.0 mmol) and triethylamine (12.26 ml, 88.0 mmol) in methylene chloride (50 ml) at 0° C. The reaction mixture was stirred overnight at RT and then concentrated in vacuo. The residue was washed with ether, dried under high vacuum for 10 min., and then redissolved in benzene (80 ml). Phosphorus pentachloride (9.24 g, 44.0 mmol) was added and the reaction mixture was heated at reflux for 1 h. The reaction mixture was diluted with ethyl acetate (250 ml) and the organic layer was washed with 5% citric acid, sat. sodium bicarbonate, and brine, and dried over MgSO₄. The solvent was evaporated in vacuo and the residue was boiled in ether for 5 min. Filtration of the solid material gave 4-(4-chlorophenyl)piperazinesulfamoyl chloride as a tan solid (40%), mp 170.5-172.0° C.

Step 2

Triethylamine (0.59 ml, 4.22 mmol) was added dropwise to a mixture of 4-(4-chlorophenyl)piperazinesulfamoyl chloride (0.56 g, 1.9 mmol), [prepared as described in Step 1 above] and methyl piperidine-2-(RS)-carboxylate HCl salt (0.38 g, 2.11 mmol) in tetrahydrofuran (15 ml) and the reaction mixture was heated at reflux. After 19 h, additional amounts of methyl piperidine-2-carboxylate HCl salt (189 mg) and triethylamine (0.15 ml) were added and the heating was continued. After 5 h, the reaction mixture was cooled, diluted with methylene chloride (40 ml), and washed with 10% citric acid, water, and brine, and dried over MgSO₄. The organics were removed in vacuo and the residue was chromatographed (SiO₂, 10-35% ethyl acetate/hexane) to yield methyl 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylate as a colorless glass (21%).

1. Proceeding as described in Step 2 above, but substituting 4-(4-chlorophenyl)piperazine with:

4-phenoxypiperidine; and

4-phenylthiopiperidine, gave respectively,

methyl 1-[4-phenoxypiperidine-1-sulfonyl]piperidine-2-(RS)-carboxylate;

methyl 1-[4-phenylthiopiperidine-1-sulfonyl]piperidine-2-(RS)-carboxylate;

2. Proceeding as described in Example 3 above, but substituting 4-(4-chlorophenyl)piperazine with:

4-(pyridin-4-ylthio)piperidine; and

4-(4-chlorobenzoyl)piperidine; and

methyl piperidine-2-(RS)-carboxylate HCl salt with methyl piperidine-2-(R)-carboxylate HCl salt, gave respectively,

methyl 1-[4-(pyridin-4-ylthio)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate; and

methyl 1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate.

3. Proceeding as described in Example 3 above, but substituting 4-(4-chlorophenyl)piperazine with 4-(5-chloropyridin-2-yl)piperazine and methyl piperidine-2-(RS)-carboxylate HCl salt with methyl 2-(RS)-amino-4-phenylbutyrate HCl salt, gave methyl 2-(RS)-{([4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}4-phenylbutyrate.

Example 4 Synthesis of tert-butyl 2-(R)-{methyl-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate ##STR15##

Step 1

N,N-dimethylformamide di-tert-butyl acetal (134 mg, 0.66 mmol) was added to a solution of 2-(R)-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyric acid (90 mg, 0.22 mmol) in toluene (2.5 ml) at 90° C. The reaction was stirred for 3 h and concentrated to give tert-butyl 2-(R)-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyric acid that was used in the next step with no further purification.

Step 2

Anhydrous potassium carbonate (152 mg, 1.1 mmol) and iodomethane (0.034 ml, 0.5 mmol) were added to a solution of tert-butyl 2-(R)-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate (100 mg, 0.22 mmol) in DMF (1.5 ml) at RT. After 3 h, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed with 0.1M HCl and brine, and dried over MgSO₄. The solvent was removed in vacuo and the residue was chromatographed (PTLC, SiO2, 25% ethyl acetate/hexane) to give tert-butyl 2-(R)-{methyl-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate as a colorless oil (63%).

Proceeding as described in Example, Step 2 above, but substituting tert-butyl 2-(R)-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate with methyl 2-(RS)-{(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-4-phenylbutyrate (prepared as described in Example 3 above) gave methyl 2-(RS)-{methyl-[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-4-phenylbutyrate.

Example 5 Synthesis of methyl 2-(R)-{(pyridin-3-ylmethyl)-[4-(4-bromophenyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate ##STR16##

Tri-n-butylphosphine (0.37 ml, 1.5 mmol) was added to a solution of methyl 2-(R)-{[4-(4-bromophenyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate (560 mg, 1.25 mmol), 3-pyridylcarbinol (0.15 ml, 1.5 mmol), and 1,1'-(azodicarbonyl)piperidine (377 mg, 1.5 mmol) in benzene (30 ml). After stirring at RT for 48 h, the reaction mixture was concentrated and the residue was triturated with ether (60 ml). After filtering off the solids, the ether layer was concentrated in vacuo and the residue was chromatographed (SiO₂, 40% ethyl acetate/hexane) to give methyl 2-(R)-{(pyridin-3-ylmethyl)-[4-(4-bromophenyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate as a colorless oil (41%).

Proceeding as described in Example 5 above, but substituting, 3-pyridylcarbinol with 3-(3-pyridyl)propanol gave methyl 2-(R)-{3-(pyridin-3-yl)propyl-[4-(4-bromophenyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate.

Example 6 Synthesis of methyl 2-(R)-[benzyl-(benzylmethylaminosulfonyl)amino]-3-methylbutyrate ##STR17##

Step 1

A solution of (D)-N-benzylvaline methyl ester (1.5 g, 6.78 mmol) and triethylamine (1.13 ml, 8.14 mmol) in ether (25 ml) was added to a solution of methylaminosulfonylchloride (0.97 g, 7.5 mmol) [prepared as described in Kloek, J. A. and Leschinsky, K. L., J. Org. Chem, 46, 4028, (1976)] in ether (25 ml) at RT. After 6 h, the reaction was quenched with 1 M HCl and the product was extracted into ether. The combined organic layers were washed with brine, dried over MgSO₄, and concentrated in vacuo to give methyl 2-(R)-[benzyl-(methylamino-sulfonyl)amino]-3-methylbutyrate as a colorless oil (86%).

Step 2

Benzyl iodide (280 mg, 1.28 mmol) and anhydrous potassium carbonate (440 mg, 3.2 mmol) were added to a solution of methyl 2-(R)-([benzyl-(methylaminosulfonyl)amino]-3-methylbutyrate (200 mg, 0.64 mmol), [prepared as described in Step 1 above] in DMF (3 ml) at RT. After 96 h, 1 M HCl was added and the product was extracted into ethyl acetate. The organic layer was washed with dilute sodium thiosulfate and brine and dried over MgSO₄. The organics were removed in vacuo and the residue was chromatographed (PTLC, SiO₂, 20% ethyl acetate/hexane) to give methyl 2-(R)-[benzyl-(benzylmethylaminosulfonyl)amino]-3methylbutyrate as a colorless oil (60%).

Example 7 Synthesis of methyl 2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}propionate ##STR18##

Step 1

A mixture of 4-(4-chlorophenyl)piperazine (6.63 g, 33.7 mmol) and sulfamide (3.89 g, 40.5 mmol) in water (10 ml) was heated at 120° C. After 96 h, the reaction mixture was cooled to RT, diluted with ethyl acetate (100 ml). Water (100 ml) was added and the reaction mixture was stirred vigorously for several minutes. The solid was filtered to give [4-(4-chlorophenyl)-piperazine-1-sulfonyl]amine as a white powder (59%), mp 218.0-220.0° C.

Step 2

A solution of potassium tert-butoxide (0.87 ml, 1M in tetrahydrofuran) was added to a solution of [4-(4-chlorophenyl)piperazine-1-sulfonyl]amine (200 mg, 0.73 mmol), [prepared as described in Step 1 above], in tetrahydrofuran (10 ml) at -60° C. After 10 min., a solution of the triflate derivative of methyl (S)-lactate (604 mg, 2.56 mmol) in tetrahydrofuran (3 ml) was added and the reaction mixture was allowed to warm to -30° C. over 30 min. The reaction mixture was quenched with saturated ammonium chloride and the product was extracted into ethyl acetate. The solvent was removed in vacuo and the residue was chromatographed (SiO₂, 30% ethyl acetate/hexane) to give methyl 2-(R)-{[-4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}propionate as a colorless oil (66%).

Proceeding as described in Example 7, Step 2 above, but substituting potassium tert-butoxide and [4-(4-chlorophenyl)piperazine-1-sulfonyl]amine with tert-butyl chloroacetate and 5-(biphenyl4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine gave tert-butyl 5-(biphenyl-4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-acetate.

Example 8 Synthesis of 2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-phenylpropionic acid ##STR19##

Step 1

Di-tert-butyl dicarbonate (2.85 g, 13 mmol) and 4-dimethylaminopyridine (90 mg, 0.7 mmol) were added to a solution of [4-(4-chlorophenyl)piperazine-1-sulfonyl]amine (3.0 g, 15.2 mmol) in tetrahydrofuran (60 ml) at RT. After 12 h, the reaction mixture was concentrated and the residue was chromatographed (SiO₂, 25% ethyl acetate/hexane) to give N-tert-butoxycarbonyl-[4-(4-chlorophenyl)piperazine-1-sulfonyl]amine as a white powder (55%).

Step 2

Diethyl azodicarboxylate (0.35 ml, 2.24 mmol) was added to a solution of triphenylphosphine (586 mg, 2.24 mmol) in tetrahydrofuran (20 ml) at -78° C. and the reaction mixture was stirred for 5 min. Tert-butyl 3-(L)-phenyl lactate (800 mg, 2.13 mmol) was added and the stirring was continued for an additional 5 min. A solution of N-tert-butoxycarbonyl-[4-(4-chlorophenyl)piperazine-1-sulfonyl]amine (757 mg, 3.41 mmol), [prepared as described in Step 1 above] in tetrahydrofuran (5 ml) was added via syringe. The reaction mixture was stirred overnight at RT and then concentrated in vacuo. The residue was chromatographed (SiO₂, 14% ethyl acetate/hexane) to give tert-butyl 2-(R)-{tert-butoxycarbonyl-[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-phenylpropionate as a pale yellow oil (88%).

Step 3

A solution of tert-butyl 2-(R)-{tert-butoxycarbonyl-[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-phenylpropionate (579 mg, 1.15 mmol), [prepared as described in Step 2 above], in methylene chloride (20 ml) was saturated with dry hydrogen chloride gas at 0° C. The reaction vessel was sealed and the reaction mixture was stirred at RT. After 72 h, the reaction mixture was vented with nitrogen and then concentrated in vacuo. The residue was treated with methylene chloride and the product was filtered to give 2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-phenylpropionic acid as a white solid (74%), mp 176.0-178.0° C.

Proceeding as described in Example 8, Step 3 above, but substituting tert-butyl 5-(biphenyl-4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-acetate (prepared as described in Example 7, Step 2 above) gave 5-(biphenyl-4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-acetate.

Example 9 Synthesis of 2-(R)-{[4-(4-chlorophenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyric acid ##STR20##

Trimethylsilyl cyanide (1.6 ml, 12.6 mmol) was added to a suspension of (D)-valine (0.89 g, 7.6 mmol) in acetonitrile and the reaction mixture was treated at reflux. After 20 min., the reaction mixture turned homogeneous. 4-(4-chlorophenoxy)piperidinesulfamoyl chloride (1.4 g, 4.5 mmol) [prepared as described in Example 3, Step 1, substituting 4-(4-chlorophenyl)piperazine with 4-(4-chlorophenoxy)piperidine] was added and the reaction mixture was stirred at reflux overnight. After concentration, methanol (25 ml) was added and the reaction mixture was stirred for 30 min. The organic layer was evaporated and the residue was chromatographed (SiO₂, 1.5% methanol/methylene chloride) to give 2-(R)-{[4-(4-chlorophenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyric acid as a colorless oil (78%).

1. Proceeding as described above but substituting (D)-valine and 4-(4-chlorophenoxy)piperidinesulfamoyl chloride with H-(D)-lysine-Cbz-OH and 4-(4-chlorophenyl)piperazinesulfamoyl chloride [prepared as described in Example 3, Step 1] respectively, gave 6-(benzyloxycarbonyl)amino-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}hexanoic acid.

2. Proceeding as described above but substituting D)-valine and 4-(4-chlorophenoxy)piperidinesulfamoyl chloride with 4-aminopiperidine-4-carboxylic acid bis-HCl salt and 4-(4-chlorobenzoyl)piperidinesulfamoyl chloride respectively, using 5 equiv. of trimethylsilyl cyanide and then quenching the crude reaction mixture with Boc anhydride in the presence of sodium hydroxide gave 1-tert-butoxycarbonyl-4-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}piperidine-4-carboxylic acid.

Example 10 Synthesis of N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-piperidine-2-(R)-carboxamide ##STR21##

Step 1

O-tert-butylhydroxylamine hydrochloride (127 mg, 1.01 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (129 mg, 0.67 mmol), N,N-dimethylaminopyridine (41 mg, 0.34 mmol), and N-methylmorpholine (0.15 ml, 1.3 mmol) were added to a solution of 1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (140 mg, 0.34 mmol), [prepared by proceeding as described in Example 9, but replacing D-valine and 4-(4-chlorophenoxy)piperidinesulfamoyl chloride with D-pipecolinic acid and 4-(4-chlorobenzoylpiperidinesulfamoyl chloride, respectively], in methylene chloride (2 ml). After stirring overnight, the reaction mixture was diluted with ethyl acetate, washed with 1M HCl, and brine, and dried over MgSO₄. The organics were evaporated in vacuo and the residue was chromatographed (PTLC, SiO₂, 40% ethyl acetate/hexane) to give N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide as a white solid (65%).

Step 2

A solution of N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (100 mg, 0.22 mmol), [prepared as described in Step 1 above], in 1,2-dichloroethane (10 ml) was cooled to -30° C. and HCl gas was bubbled through it for 10 min. The reaction vessel was then sealed and stirred at RT. After 2 days, the reaction mixture was vented with nitrogen and then concentrated in vacuo. The residue was chromatographed (PTLC, SiO₂, 10% methanol/methylene chloride) to give N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide as a white solid (51%), mp 84.4-86.4° C.

Proceeding as described in Example 10 Step 1 above but substituting 1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid with 1-tert-butoxycarbonyl-4-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}piperidine-4-carboxylic acid [prepared as described in Example 9 above] gave N-tert-butoxy-1-tert-butoxycarbonyl-4-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}piperidine-4-carboxamide.

Example 11 Synthesis of N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide ##STR22##

Step 1

A solution of lithium hydroxide monohydrate (0.35 g, 8.3 mmol) in water (5 ml) was added to a solution of methyl (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1 sulfonyl]amino}-3-methylbutyrate (1.7 g, 4.2 mmol), [prepared as described in Example 2], in methanol/tetrahydrofuran (1:1, 25 ml) and the reaction mixture was warmed to 45° C. After stirring overnight, reaction mixture was adjusted to pH 6 using 1M HCl and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. The residue was chromatographed (SiO₂, 2% methanol/methylene chloride) to give 2-(R)-{[4-(5-chloropyridin-2-yloxy)piperidine-1-sulfonyl]amino}-3-methylbutyric acid as a white gummy solid (66%).

Step 2

Oxalyl chloride (0.58 ml, 6.7 mmol) and DMF (few drops) were added to a solution of (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1sulfonyl)amino}-3-methylbutyric acid (1.05 g, 2.7 mmol), [prepared as described in Step 1 above], in methylene chloride (85 ml) and the reaction mixture was stirred overnight at RT. After removal of the organics, the residue was redissolved in methylene chloride (40 ml) and N,O-bis-trimethylsilylhydroxylamine (1.7 g, 9.4 mmol) was added. After 3 h, the reaction was concentrated, methanol (20 ml) was added and after stirring for an additional 30 min., the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried over MgSO₄, and concentrated. Chromatography (SiO₂, 1-2% methanol/methylene chloride) gave N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl-oxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide as a white solid (35%), mp 97.0-98.4° C.

1. Proceeding as described in Example 11 above, but substituting methyl (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1 sulfonyl]amino}-3-methylbutyrate with:

methyl 2-(R)-{[4-(4-chlorophenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyrate (see Example 2);

methyl 2-(R)-{[4-(4-fluorophenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyrate (see Example 2);

methyl 2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-methylbutyrate;

methyl 2-(R)-{[4-[(4-benzyloxy)phenyl]piperazine-1-sulfonyl]amino}-3-methylbutyrate (see Example 2);

methyl 2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-3-methylbutyrate (see Example 2);

methyl 2-(R)-{[4-(2-phenylbenzoxazol-5-yl)piperazine-1-sulfonyl]amino}-3-methylbutyrate (see Example 2);

methyl 2-(R)-{[4-(4-phenylimidazol-2-yl)piperidine-1-sulfonyl]amino}-3-methylbutyrate (see Example 2);

methyl 1-[4-phenoxypiperidine-1-sulfonyl]piperidine-2-(RS)-carboxylate (see Example 3 above);

methyl 2-(RS)-{methyl-[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-4-phenylbutyrate (see Example 4 above);

methyl 2-(R)-{3-(pyridin-3-yl)propyl-[4-(4-bromophenyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate (see Example 5 above); and

methyl 2-(R)-{(pyridin-3-ylmethyl)-[4-(4-bromophenyl)piperidine-1-sulfonyl]amino}-3-methylbutyrate (see Example 5 above), gave respectively,

N-hydroxy-2-(R)-{[4-(4-chlorophenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide;

N-hydroxy-2-(R)-{[4-(4-fluorophenoxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide;

N-hydroxy-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-3-methylbutyramide;

N-hydroxy-2-(R)-{[4-(4-benzyloxy)phenyl]piperazine-1-sulfonyl]amino}-3-methylbutyramide;

N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-3-methylbutyramide;

N-hydroxy-2-(R)-{[4-(2-phenylbenzoxazol-5-yl)piperazine-1-sulfonyl]amino}-3-methylbutyramide;

N-hydroxy-2-(R)-{[4-(4-phenylimidazol-2-yl)piperidine-1-sulfonyl]amino}-3-methylbutyramide;

N-hydroxy-1-[4-phenoxypiperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide;

N-hydroxy-2-(RS)-{methyl-[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-4-phenylbutyramide;

N-hydroxy-2-(R)-{3-(pyridin-3-yl)propyl-[4-(4-bromophenyl)piperidine-1-sulfonyl]amino}-3-methylbutyramide; and

N-hydroxy-2-(R)-{(pyridin-3-ylmethyl)-[4-(4-bromophenyl)piperidine-1-sulfonyl]amino}-3-methylbutyramide.

2. Proceeding as described in Example 11, Step 1 above, but substituting methyl (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1 sulfonyl]amino}-3-methylbutyrate with methyl 1-[4-(pyridin-4-ylthio)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate [prepared as described in Example 3 above] gave 1-[4-(pyridin-4-ylthio)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid.

Example 12 Synthesis of N-hydroxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]-piperidine-2-(RS)-carboxamide ##STR23##

Step 1

A solution of methyl 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylate (164 mg, 0.41 mmol), [prepared as described in Example 3] and NaOH (33 mg, 0.82 mmol) in methanol/water (5 ml of 9:1 ratio) was heated at reflux. After 2 h, the reaction mixture was concentrated in vacuo, diluted with water (5 ml) and extracted with diethyl ether. The aqueous phase was acidified to pH 3 with 5% potassium bisulfate solution and the product was extracted into ethyl acetate. The organic phase was washed with brine, dried over MgSO₄, and concentrated to yield 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid as a foam (125 mg, 79%).

Step 2

O-(tert-butyldimethylsilyl)hydroxylamine (57 mg, 0.39 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol) were added to a solution of 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid (100 mg, 0.26 mmol), [prepared as described above] in methylene chloride (4 ml). The reaction mixture was stirred overnight at RT and then diluted with methylene chloride. The solution was washed with water, 10% citric acid, and brine, and dried over MgSO₄. After the organics were removed the residue was chromatographed (SiO₂, 20-30% ethyl acetate/hexane) to give N-tert-butyldimethylsiloxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide as a colorless foam (56%).

Step 3

Trifluoroacetic acid (few drops) was added to a solution of N-tert-butyldimethylsiloxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide (63 mg, 0.12 mmol), [prepared as described in Step 2 above], in methylene chloride (2 ml) and the reaction mixture was stirred at RT for 45 min. The organics were removed in vacuo and the residue was dissolved in methylene chloride (25 ml) and the washed with sat. sodium bicarbonate, brine, and dried over MgSO₄. The solvent was removed in vacuo to give a foam which was redissolved in a minimum amount of methylene chloride. Diethyl ether was added and the resulting white precipitates were filtered to give N-hydroxy-1-[4-(4-chlorophenyl)-piperazine-1-sulfonyl]-piperidine-2-(RS)-carboxamide (67%).

1. Proceeding as described in Example 12 above, but substituting methyl 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylate with methyl 1-[4-phenylthiopiperidine-1-sulfonyl]piperidine-2-(RS)-carboxylate [prepared as described in Example 3 above] gave N-hydroxy-1-[4-phenylthiopiperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide.

2. Proceeding as described in Example 12, Steps 2 and 3 above, but substituting 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid with 1-[4-(pyridin-4-ylthio)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid [prepared as described in Example 11 above) gave N-hydroxy-1-[4-(pyridin-4-ylthio)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide.

Example 13 Synthesis of N-hydroxy-2-(R)-{benzyl-[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}propionamide ##STR24##

A solution of potassium hydroxide (1.6 g, 29.2 mmol) in methanol (9.8 ml) was added to a solution of hydroxylamine hydrochloride (1.02 g, 14.6 mmol) in methanol (9.8 ml) at 0° C. After 5 min., a solution of methyl 2-(R)-{benzyl-[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-propionate (1.101 g, 2.44 mmol) in methanol (9.8 ml), [prepared as described in Example 2, Step, 2, but replacing D-valinesulfamoyl chloride methyl ester and 4-(5-chloropyridin-2-yloxy)piperidine with D-alaninesulfamoyl chloride methyl ester and 4-(4-chlorophenyl)-piperazine respectively, followed by benzylation as described in Example 4] was added and the reaction temperature was allowed to rise to RT. After 5 h, the reaction mixture was diluted with methylene chloride (147 ml) and neutralized with 10% aqueous HCl. The solvent was removed in vacuo and the residue was dissolved in methanol. The insoluble salts were filtered off and N-hydroxy-2-(R)-{benzyl-[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}-propionamide was isolated using reverse phase preparative HPLC (20-70% acetonitrile/0.1% aqueous trifluoroacetic acid) as a crystalline solid (23%).

Proceeding as described in Example 13 above, but substituting methyl 2-(R)-{benzyl-[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}propionate with methyl 2-(R)-{[4-[(4-chorobenzylaminocarbonyl)methyl]piperidine-1-sulfonyl]amino}propionate [prepared as described in Example 2, above] gave N-hydroxy-2-(R)-{[4-[(4-chlorobenzylaminocarbonyl)methyl]piperidine-1-sulfonyl]amino}propionamide.

Example 14 Synthesis of N-hydroxy-4-benzyloxycarbonyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(RS)-carboxamide ##STR25##

Step 1

To a solution of 4-(5-fluoroindol-3-yl)-1,2,3,6-tetrahydropyridine (3.68 g, 17.0 mmol) [prepared as described in Guillaume, J., Dumont, C., Laurent, J., Nedelec, L., Eur. J. Med. Chem., 22, 33, (1987)] in argon deoxygenated methanol (80 ml) was added 10% Pd-C (740 mg) and the resulting mixture was stirred under an atmosphere of hydrogen (1 atm.). After 3 h, the reaction mixture was degassed under argon, di-tert-butyl dicarbonate (5.03 g, 23.0 mmol) was added, and the hydrogenation was continued for an additional 21 h. The argon degassed slurry was filtered through Celite, washed with methylene chloride, and the filtrate was concentrated in vacuo. Recrystallization of the residue from methylene chloride/hexanes gave N-tert-butoxycarbonyl-4-(5-fluoroindol-3-yl)piperidine (65%) as a white solid. The mother liquor (2 g) was chromatographed (SiO₂, 15% ethyl acetate/hexanes) to give an additional 0.9 g of product (12%).

Step 2

Sodium hydride (96 mg, 4.07 mmol) was added to a solution of N-tert-butoxycarbonyl-4-(5-fluoroindol-3-yl)piperidine (1.28 g, 4.07 mmol), [prepared as described in Step 1, above] in DMF (6 ml) at 0° C. and the reaction mixture was stirred for 30 min. 2-Trimethylsilylethanesulfonyl chloride (820 mg, 4.07 mmol) was added and the reaction mixture was slowly warmed to RT over 30 min. After 2.5 h, the reaction mixture was quenched with water (10 ml) and the product was extracted into methylene chloride. The combined organic layers were dried over MgSO₄ and concentrated in vacuo. Due to incomplete reaction the above steps were repeated on the isolated crude reaction mixture. The final residue was chromatographed (PTLC, SiO₂, 20% ethyl acetate/hexanes) to afford N-tert-butoxycarbonyl-4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine (84%) as a clear oil.

Step 3

To a solution of N-tert-butoxycarbonyl-4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine (1.33 g, 2.73 mmol), [prepared as described in Step 2, above] in methylene chloride (3 ml), was added trifluoroacetic acid (4 ml). After 2 h, the reaction mixture was concentrated in vacuo and the residue was partitioned between methylene chloride (50 ml) and of 1M NaOH (10 ml). The organic layers were dried over MgSO₄ and concentrated in vacuo to afford 4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine (100%). This material was used in the next step without further purification.

Step 4

To a solution of 4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine (1.05 g, 2.73 mmol), [prepared as described in Step 3, above] and triethylamine (0.837 ml, 6.01 mmol) in methylene chloride (14.4 ml) at 0° C., was added chlorosulfonic acid (0.191 ml, 2.87 mmol) over 5 min. The reaction mixture was stirred overnight at RT and then concentrated in vacuo. The residue was diluted with benzene (14.4 ml), phosphorous pentachloride (568 mg, 2.73 mmol) was added and the resulting mixture was heated at reflux for 2 h. The heterogeneous reaction mixture was cooled to RT and filtered through a plug of silica gel (20 g) using 30% ethyl acetate/hexanes (250 ml). The eluent was washed with 2.4 N aqueous HCl, dried over MgSO₄, and concentrated in vacuo to afford 4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidinesulfamoyl chloride (83%) as a pale yellow foam.

Step 5

To a solution of piperazic acid ammonium salt (7.5 g, 57 mmol) and triethylamine (17 ml, 122 mmol) in of water (22 ml) at 0° C., was added a solution of O-carbobenzyloxysuccinimide (14.4 g, 57.8 mmol) in dioxane (22 ml) over a 1.25 h period. The reaction mixture was allowed to warm to RT over 2 h and the stirring was continued. After 20 h, the reaction mixture was concentrated in vacuo and the residue was triturated with warm ethanol, filtered, and washed with ether to afford 4-benzyloxycarbonylpiperazine-2-(RS)-carboxylic acid ammonium salt (63%) as a light tan solid. This material was used without further purification.

Step 6

To a slurry of 4-benzyloxycarbonylpiperazine-2-(RS)-carboxylic acid ammonium salt (503 mg, 1.90 mmol), [prepared as described in Step 5 above] in acetonitrile (3 ml) at 0° C., was added trimethylsilylcyanide (0.476 ml, 3.80 mmol) and the reaction mixture warmed to RT over 10 min. 4-[5-Fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidinesulfamoyl chloride (300 mg, 0.62 mmol) [prepared as described in Step 4 above] was added in one portion, and the mixture was heated at reflux for 14 h. The solution was cooled to RT, methanol (2 ml) was added, and the resulting heterogeneous mixture was stirred for 10 min. The slurry was filtered through a plug of silica gel (20 g) using 10% methylene chloridehexanes (250 ml), the filtrate was concentrated, and the residue was chromatographed (PTLC, SiO₂, 10% methanol/methylene chloride) to afford 4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxylic acid (63%) as a yellow foam.

Step7

To a solution of 4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxylic acid(288 mg, 0.40 mmol), [prepared as described in Step 6 above] in methylene chloride (5 ml) at 0° C. were added a few drops of DMF and oxalyl chloride (89 ml, 1.0 mmol). The reaction mixture was warmed to RT over 1 h, and stirring was continued for an additional 14 h. The reaction mixture was concentrated in vacuo, redissolved in methylene chloride (5 ml) and cooled to 0° C. N,O-bis-trimethylsilyl hydroxylamine (0.304 ml, 1.42 mmol) added, the reaction was warmed to RT, stirred for 3 h, and then recooled to 0° C. After adding methanol (3 ml), the mixture was stirred for an additional 30 min., and then concentrated in vacuo. The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml), the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over MgSO₄, and concentrated in vacuo to afford N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide as a yellow foam (250 mg, 86%). The residue was used without further purification.

Step 8

Tetrabutylammonium fluoride (0.194 ml, 1M solution in tetrahydrofuran) was added to a solution of N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide (0.067 mg, 0.093 mmol), [prepared as described in Step 7 above] in tetrahydrofuran (1.6 ml). The reaction mixture was heated at 45° C. for approx. 20 min., and then quenched with glacial acetic acid (0.011 ml, 0.194 mmol). The reaction mixture was concentrated and the residue was chromatographed by preparatory TLC (10% methanol/methylene chloride) to give N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoroindol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide (71%), mp 85.7-89.7° C.

Example 15 Synthesis of N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide ##STR26##

Step 1

To a solution of N-benzyloxycarbonyl-4-piperidone (20.2 g, 90.6 mmol) in methylene chloride (600 ml) at 0° C. was added trimethylsilyl trifluoromethanesulfonate (35.1 ml, 181.2 mmol) followed by the slow dropwise addition of a solution of 4,5,6,7-tetrafluoroindole (17.1 g, 90.6 mmol) in methylene chloride (300 ml) over 2.5 h. After 1.5 h, triethylsilane (57.9 ml, 362.4 mmol) was added and the reaction was allowed to warm to RT over 30 min. The reaction mixture was quenched with sat. sodium bicarbonate and the separated organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was partitioned between 50% acetonitrile/hexanes (1400 ml) and the separated acetonitrile layer was concentrated in vacuo. The solid residue was recrystallized from absolute EtOH to afford N-benzyloxycarbonyl-4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine (66%) as a white solid.

Step 2

To a solution of N-benzyloxycarbonyl-4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine (20.0 g, 49.21 mmol) [prepared as described in Step 1 above] in argon deoxygenated 80% ethanol/tetrahydrofuran (800 ml) was added 10% Pd-C (5 g), and the resulting mixture was stirred under a hydrogen atmosphere (1 atm) for 3 h. The mixture was degassed under argon, filtered through Celite, and concentrated in vacuo. The solid residue was recrystallized from methylene chloride/hexane to afford 4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine (90%) as a white solid.

Step 3

Chlorosulfonic acid (2.9 ml, 44.10 mmol) was added dropwise over 5 min., to a solution of 4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine (12.0 g, 44.10 mmol) [prepared as described in Step 2 above] and triethylamine (12.9 ml, 92.61 mmol) in methylene chloride (220 ml) at 0° C. The reaction was allowed to warm to RT overnight with stirring and then concentrated in vacuo. The residue was diluted with benzene (220 ml), phosphorous pentachloride (9.74 g, 46.78 mmol) was added and the resulting mixture was heated to reflux for 2 h. The heterogeneous reaction mixture was cooled to RT and filtered through a pad of silica gel using 30% ethyl acetate-hexanes as the eluant. The resulting filtrate was washed with 2.4 M aqueous hydrochloric acid, dried over MgSO₄ and concentrated in vacuo to give 4-(4,5,6,7-tetrafluoro-indol-3-yl)piperidinesulfamoyl chloride (99%) as an orange oil.

Step 4

To a slurry of 4-(N)-tert-butoxycarbonylpiperazine-2-(R)-carboxylic acid (34 g, 148 mmol) [prepared as described in Bigge, C. F.; Hays, S. J.; Novak, P. M.; Drummnond, J. T.; Johnson, G.; Bobovski, T. P. Tet. Lett. 5193, (1989)] in acetonitrile (500 ml) was added trimethylsilylcyanide (47.7 ml, 381 mmol) at 0° C. The reaction mixture warmed to RT over 50 min., and 4-(4,5,6,7-tetrafluoroindol-3-yl)piperidinesulfamoyl chloride (16.38 g, 44.1 mmol) [prepared as described in Step 3 above] was added in one portion. The reaction mixture was heated at reflux for 36 h and then cooled to RT. Methanol (10 ml) was added, and the resulting heterogeneous mixture was stirred for 10 min. The slurry was filtered through a pad of silica gel using 10% methylene chloride/hexanes as the eluant. The filtrate was concentrated in vacuo and the residue was chromatographed (SiO₂, 10% methanol/methylene chloride) to afford 25.0 g of 4-tert-butoxycarbonyl-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxylic acid which was immediately dissolved in methylene chloride (400 ml) and cooled to 0° C. To this solution was added O-benzylcarboxamide hydroxylamine (15.92 g, 129.5 mmol), 4-dimethylaminopyridine (5.27 g, 43.15 mmol) and 4-methylmorpholine (14.2 ml, 129.5 mmol), followed by the slow addition of 1-ethyl-3-(3-dimethylamninopropyl)carbodiimide (17.37 g, 90.62 mmol) over 15 min. The reaction mixture was allowed to warm to RT overnight and 2 M aqueous HCl solution was added. The separated methylene chloride layer was dried over MgSO₄, and concentrated in vacuo. The residue was chromatographed (SiO₂, 1% methanol/methylene chloride) to afford N-benzyloxy-4-tert-butoxycarbonyl-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (78%) as a yellow foam.

Step 5

To a solution of N-benzyloxy-4-tert-butoxycarbonyl-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (24.40 g, 36.40 mmol) [prepared as described in Step 4 above] in methylene chloride (90 ml) was added trifluoroacetic acid (60 ml). The reaction mixture was stirred for 2 h, concentrated in vacuo, and partitioned between ethyl acetate (500 ml) and sat. sodium bicarbonate (200 ml). The aqueous layer was washed with ethyl acetate and the combined organic layers were dried over MgSO₄ and concentrated in vacuo. The residue was dissolved in ethyl acetate (40 ml) and slowly added to hexane (200 ml) with vigorous stirring. The resulting slurry was filtered to afford 20.65 g of N-benzyloxy-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide as a white solid.

Step 6

A solution of N-benzyloxy-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (12 g, 21.08 mmol) [prepared as described in Step 5 above] and 2,6-luitidine (4.0 ml, 33.73 mmol) in methylene chloride (100 ml) was treated with dimethylcarbamoyl chloride (3.10 ml, 33.73 mmol) and stirred for 14 h. The reaction mixture was washed with 3M aqueous HCl solution (20 ml), brine, dried over MgSO₄ and concentrated in vacuo. The residue was chromatographed (SiO₂, 30% ethyl acetate/hexane then 5% methanol/methylene chloride). The product was dissolved in ethyl acetate (25 ml) and added dropwise to hexane (200 ml) with vigorous stirring. The solid was filtered to give N-benzyloxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (67%) as a white solid.

Step 7

A solution of N-benzyloxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (8.90 g, 13.97 mmol) [prepared as described in Step 6 above] in argon deoxygenated 80% ethanol/tetrahydrofuran (470 ml) was treated with 10% Pd/C (3.5 g) and stirred under a hydrogen atmosphere (1 atm) for 45 min. The reaction was degassed under argon, filtered through Celite, and the filtrate was concentrated in vacuo. Ethyl acetate (5 ml) was added and the solution was added dropwise to hexane (250 ml) with vigorous stirring. The solid was filtered to afford N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (96%) as a white solid.

1. Proceeding as described in Example 15, Step 5, but substituting N-benzyloxy-4-tert-butoxycarbonyl-1-[4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide with N-tert-butoxy-1-tert-butoxycarbonyl-4-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}piperidine-4-carboxamide [prepared as described in Example 10, above] gave N-tert-butoxy-4-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}piperidine-4-carboxamide.

2. Proceeding as described in Example 15, Step 4, but substituting O-benzylhydroxylamine and 4-(4,5,6,7-tetrafluoroindol-3-yl)piperidine sulfamoyl chloride with O-tert-butylhydroxylamine and 4-(4-chlorobenzoyl)piperidinesulfamoyl chloride respectively, gave N-tert-butoxy-tert-butoxycarbonyl-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide. This material was converted to N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide by carrying out the hydrolysis with 15-20% trifluoroacetic acid in methylene chloride and closely monitoring the reaction by TLC.

Example 16 Synthesis of N-hydroxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide ##STR27##

Step 1

Chlorosulfonic acid (14.25 ml, 214.5 mmol) was added dropwise to a 0° C. solution of 2-(R)-methoxycarbonylpiperidine HCl salt (35.0 g, 195 mmol) and triethylamine (86.96 ml, 624 mmol) in methylene chloride (550 ml). The reaction was stirred for 5 h, concentrated in vacuo, and dried under high vacuum overnight. The resulting yellow solid was suspended in benzene (500 ml) and phosphorus pentachloride (40.6 g, 195 mmol) was added. The reaction mixture was heated at reflux with vigorous stirring for 5 h and concentrated in vacuo. The resulting slurry was stirred with ether (300 ml) and filtered. The solid was washed with additional ether (300 ml) and the combined filtrate was washed with water, brine, dried over MgSO₄, and concentrated to give 2-(R)-methoxycarbonylpiperidine-1-sulfamoyl chloride (88%) as a dark yellow oil that was used without further purification.

Step 2

A solution of 4-(5-fluoroindol-3-yl)piperidine (0.40 g, 1.83 mmol) and triethylamine (1.02 ml, 7.33 mmol) in tetrahydrofuran (13 ml) was treated with 2-(R)-methoxycarbonylpiperidine-1-sulfamoyl chloride (0.66 g, 2.75 mmol) [prepared as described above in Step 1] and the reaction mixture was stirred at RT for 24 h. The reaction was quenched with sat. ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO₄, and concentrated. The residue was chromatographed (PTLC, SiO₂, 20%-35% ethyl acetate/hexanes) to give methyl 1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate (61%) as a clear oil. This material was converted to 1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid by proceeding as described in Example 11, Step 1 but substituting methyl (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1sulfonyl]amino}-3-methylbutyrate with methyl 1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate.

Step 3

To a solution of 1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (0.46 g, 1.12 mmol) [prepared as described Step 2 above] in methylene chloride (10 ml) was added 0-benzylhydroxylamine hydrochloride salt (0.54 g, 3.36 mmol), followed by 4-dimethylaminopyridine (0.15 g, 1.23 mmol), 4-methylmorpholine (0.38 ml, 3.47 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.43 g, 2.24 mmol). The reaction was stirred at RT for 2 h, diluted with methylene chloride (50 ml) and washed with 1M HCl. The organic layer was washed with brine, dried over MgSO₄, and concentrated to give N-benzyloxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (95%) as a clear oil. This material was used without further purification.

Step 4

Anhydrous potassium carbonate (736 mg, 5.33 mmol) and iodomethane (0.133 ml, 2.13 mmol) were added to a solution of N-benzyloxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (549 mg, 1.07 mmol) [prepared as described in Step 3 above] in dimethylformamide (11 ml) at RT. After 2 h, the reaction mixture was diluted with ethyl acetate (50 ml) and then washed with 0.1 M HCl, brine and dried over MgSO₄. The solvent was removed in vacuo and the residue was chromatographed (PTLC, SiO₂, 40% ethyl acetate/hexanes) to give N-benzyloxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (71%) as a white solid.

Step 5

A suspension of 10% Pd/C (0.20 g) and N-benzyloxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (0.40 g, 0.75 mmol) [prepared as described in Step 4 above] in 80% ethanol/tetrahydrofuran (6 ml) was stirred under a hydrogen atmosphere (1 atm) for 70 min. The reaction was degassed with nitrogen, filtered through Celite and the filtrate was concentrated in vacuo. The residue was chromatographed (PTLC, SiO₂, 10% methanol/methylene chloride) to give N-hydroxy-N-methyl-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (83%) as a white solid.

1. Proceeding as described in Example 16, Step 2 but substituting 2-(R)-methoxycarbonylpiperidine-1-sulfamoyl chloride and 4-(5-fluoroindol-3-yl)piperidine with 2-(RS)-ethoxycarbonylpiperidine-1-sulfamoyl chloride and 4-(6-fluorobenzisoxazol-3-yl)piperidine ((prepared as described in Strupczewski, J. T., Allen, R. C., Gardner, B. A., Schmid, B. L., Stache, U., Glamkowski, E. J., Jones, M. C., Ellis, D. B., Huger, F. P., Dunn, R. W., J. Med. Chem., 28, 761, (1985)) respectively, gave ethyl 1-[4-(6-fluorobenzisoxazol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxylate. This material was converted to N-hydroxy-1-[4-(6-fluorobenzisoxazol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide by following procedure described in Example 11.

2. Proceeding as described in Example 16, Step 2 but substituting 4-(5-fluoroindol-3-yl)piperidine with 1,2,3,4-tetrahydro-beta-carboline gave methyl 1-[1,2,3,4-tetrahydro-beta-carboline-2-sulfonyl]piperidine-2-(R)-carboxylate which was converted to N-hydroxy-1-[1,2,3,4-tetrahydro-beta-carboline-2-sulfonyl]piperidine-2-(R)-carboxamide by following Example 16, Steps 3 and 5 above.

3. Proceeding as described in Example 16, Step 3 above, but substituting of 1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid with 5-(biphenyl-4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-acetate [prepared as described in Example 8 above] gave N-benzyloxy-5-(biphenyl-4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-acetamide which was converted to N-hydroxy-5-(biphenyl-4-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidine-2-acetamide by following Example 16, Step 5.

Example 17 Synthesis of N-hydroxy-1-[4-(5-hydroxyindol-3-yl)piperidine-1-sulfonyl-piperidine-2-(RS)-carboxamide ##STR28##

Step 1

Potassium tert-butoxide (2.81 g, 25.02 mmol) was added to a solution of 5-hydroxyindole (1.11 g, 8.34 mmol) in tert-butyl alcohol. 1-Benzyloxycarbonyl-4-piperidone (3.89 g, 16.67 mmol) was added to the purple reaction mixture at RT. After 16 h, the reaction mixture was diluted with ethyl acetate (100 ml) and washed with saturated sodium bicarbonate, brine, dried over MgSO₄ and concentrated in vacuo. The residue was chromatographed (SiO₂, 25-45% ethyl acetate/hexanes) to give 4-(5-hydroxyindol-3-yl)-1,2,3,6-tetrahydropyridine as a white solid (92%).

Step 2

Tetrahydrofuran (96 ml) was added to an argon degassed flask containing 4-(5-hydroxyindol-3-yl)-1,2,3,6-tetrahydropyridine (2.67 g, 7.64 mmol), [prepared as described in Step 1, above] and 10% Palladium on carbon (2.67 g). The reaction mixture was hydrogenated for 15 h at 60 psi on a parr apparatus. The reaction mixture was degassed, filtered through Celite and concentrated in vacuo to give 4-(5-hydroxyindol-3-yl)piperidine as a white solid (95%). This material was converted to 1-[4-(5-hydroxyindol-3-yl)-piperidine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid (99%) by proceeding as described in Example 16, Step 2 above, by substituting 4-(5-fluoroindol-3-yl)piperidine and 2-(R)-methoxycarbonylpiperidine-1-sulfamoyl chloride with 4-(5-hydroxyindol-3-yl)piperidine and 2-(RS)- methoxycarbonylpiperidine-1-sulfamoyl chloride respectively.

Step 3

N-Hydroxysuccinimide (0.181 g, 1.57 mmol), 4-dimethylaminopyridine (96 mg, 0.78 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.33 g, 1.73 mmol) were added to a solution of 1-[4-(5-hydroxyindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid (0.32 g, 0.78 mmol) [prepared as described in Step 2 above] in 30% dimethylformamide/methylene chloride (5.5 ml). After stirring at RT for 2 h, the reaction was diluted with methylene chloride (50 ml) and washed with 1M HCl, brine and dried over MgSO₄. The organics were evaporated in vacuo and the residue was dissolved in 50% ethyl acetate/methanol (13.4 ml). This solution was added to a solution of 50% aqueous hydroxylamine (6.7 ml, 109 mmol) in methanol (6.7 ml) at -30° C. with vigorous stirring. After 10 min., the reaction mixture was quenched with 1M HCl (final pH=3) and then concentrated in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with brine and dried over MgSO₄. The organics were evaporated in vacuo and the residue was chromatographed (SiO₂, 10% methanol/methylene chloride) to give N-hydroxy-1-[4-(5-hydroxyindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxamide (22%) as a white solid.

Proceeding as described in Example 17, Step 3, but substituting 30% dimethylformamide/methylene chloride with 100% methylene chloride and 1-[4-(5-hydroxyindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid with 6-(benzyloxycarbonyl)amino-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}hexanoic acid [prepared as described in Example 9 above] gave N-hydroxy-6-(benzyloxycarbonyl)-amino-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}hexanoamide.

Example 18 Synthesis of N-hydroxy-1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide ##STR29##

Step 1

To a solution of N-tert-butoxycarbonyl-4-piperidone (7.77 g, 39 mmol) in methylene chloride (200 ml) at 0° C. was added trifluoroacetic acid (70 ml) and the resulting solution was allowed to warm to RT over 1.5 h. The reaction mixture was concentrated in vacuo, dried under high vacuum for 3 h and 25% water/dioxane (70 ml) was added. To this solution was added sodium carbonate (8.3 g, 78 mmol) and 2-(R)-methoxycarbonylpiperidine-1-sulfamoyl chloride (3.5 g, 15.6 mmol) and the resulting suspension was rapidly stirred at RT. After 24 h, the reaction mixture was filtered and the filtrate was diluted with ethyl acetate (150 ml), water (200 ml) and acidified with 1 M HCl. The aqueous layer was extracted with ethyl acetate and the combined organics were washed with brine, dried over MgSO₄ and concentrated to give methyl 1-(4-piperidone-1-sulfonyl)piperidine-2-(R)-carboxylate (96%) as a pale yellow oil that was used without further purification.

Step 2

A solution of N-triisopropylsilylpyrrole (1.62 ml, 6.57 mmol) in methylene chloride (50 ml) was added to a solution of methyl 1-(4-piperidone-1-sulfonyl)piperidine-2-(R)-carboxylate [prepared as described in Step 1 above] and trimethylsilyl trifluoromethanesulfonate (2.54 ml, 13.14 mmol) in methylene chloride (110 ml) at -78° C. over 1.5 h. Triethylsilane (4.2 ml, 26.28 mmol) was added and after 2 h the reaction mixture was washed with saturated sodium bicarbonate, brine and dried over MgSO₄. The solvent was evaporated in vacuo, and the residue was chromatographed (SiO₂, 10-20% ethyl acetate/hexanes) to give methyl 1-[4-(1-triisopropylsilylpyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate which was used in the next step without further purification.

Step 3

Tetrabutylammonium fluoride (2.45 ml, 2.45 mmol) was added to a solution of methyl 1-[4-(1-triisopropylsilylpyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate (2.5 g, 4.89 mmol) [prepared as described in Step 2 above] in tetrahydrofuran (48 ml) at 0° C. After 30 min., the reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO₄, and concentrated in vacuo. The residue was chromatographed (SiO₂, 15-40% ethyl acetate/hexanes) to yield methyl 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate (31%) as a clear oil. This material was converted to 1-[4-(pyrrol-3-yl)-piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (93%) by proceeding as described in Example 11, Step 1, but substituting methyl (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1 sulfonyl]amino}-3-methylbutyrate with methyl 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylate.

Step 4

Proceeding as described in Example 17, Step 4, but substituting 30% dimethylformamide/methylene chloride with 100% methylene chloride and 1-[4-(5-hydroxyindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid with 1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid [prepared as described in Step 3 above] gave N-hydroxy-1-[4-(pyrrol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide (21%) as a white solid.

Example 19 Synthesis of N-hydroxy-1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide ##STR30##

Step 1

A solution of 5-cyanoindole (10.00 g, 70.34 mmol) in acetonitrile (120 ml) was added to a solution of 1-benzyloxycarbonyl-4-piperidone (8.20 g, 35.17 mmol) and trimethylsilyl trifluoromethanesulfonate (6.80 ml, 35.17 mmol) in acetonitrile (230 ml) via addition funnel at 0° C. over 1.5 h. Triethylsilane (4.2 ml, 26.28 mmol) was added at 0° C. and reaction mixture was allowed to gradually warm to RT over 2 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine, dried over MgSO₄, and concentrated in vacuo. The residue was diluted with acetonitrile (300 ml) and hexanes (200 ml) and stirred for 20 min. The organics were removed in vacuo and the residue was chromatographed (SiO₂, 20-40% ethyl acetate/hexanes) to give 1-benzyloxycarbonyl-4-(5-cyanoindol-3-yl)piperidine as a white crystalline solid (59%).

Step 2

Sodium hydride (115 mg, 4.8 mmol) was added to a solution of 1-benzyloxycarbonyl-4-(5-cyanoindol-3-yl)piperidine (1.5 g, 4.17 mmol) [prepared as described in Step 1 above] in dimethylformamide (12 ml) at 0° C. After 30 min., methanesulfonyl chloride (0.81 ml, 10.43 mmol) was added and after stirring for 2.5 h the reaction mixture was allowed to warm to RT over 1 h. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water, brine and dried over MgSO₄. The organics were evaporated in vacuo and the residue was chromatographed (PTLC, SiO2, 40% ethyl acetate/hexanes) to give 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (54%) as a pale yellow oil.

Step 3

10% Palladium on carbon (0.49 g) was added to a solution of 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (0.98 g, 2.24 mmol) [prepared as described in Step 2 above] in 80% ethanol/tetrahydrofuran (10 ml) under an argon atmosphere. The reaction mixture was stirred under an atmosphere of hydrogen gas (1 atm) for 2 h. The reaction mixture was degassed, filtered through Celite and concentrated in vacuo to give 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine (97%) as a white solid. This material was converted to N-hydroxy-1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxamide by converting it to 4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl chloride by following Example 16, Step 1, coupling the sulfonyl chloride with (R)-pipecolinic acid (L)-tartrate salt to give 1-[4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid (86%) by following Example 14, Step 6 and then converting the acid to the final compound by following Example 16, Steps 3 and 5; mp: 143.3-143.9° C.

Proceeding as described in Example 19, Step 3, but substituting 1-benzyloxycarbonyl-4-(5-cyano-1-methanesulfonylindol-3-yl)piperidine with 1-benzyloxycarbonyl-4-[5-cyano-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine [prepared as described in Example 14, Step 2, by substituting 1-benzyloxycarbonyl-4-(5-cyanoindol-3-yl)piperidine for N-tert-butoxycarbonyl-4-(5-fluoroindol-3-yl)piperidine] gave 4-[5-cyano-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine.

Example 20 Synthesis of N-hydroxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]-4-(N,N-dimethylaminosulfonyl)piperazine-2-(R)-carboxamide ##STR31##

Step 1

N,N-Dimethylsulfamoyl chloride (0.14 ml, 1.31 mmol), sodium carbonate (0.46 g, 4.37 mmol) and water (3 ml) were added to a solution of N-benzyloxy-1-{4-[5-cyano-1-(2-trimethylsilylethanesulfonyl)indole-3-yl]piperidine-1-sulfonyl}-1,4-piperazine-2-(R)-carboxamide (0.6 g, 0.87 mmol) [prepared from 4-[5-cyano-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine by following the procedures described in Example 19, Step 3, Example 14, step 4 and Example 15, Steps 4 and 5] in dioxane (6 ml) at RT. After 1 h, the reaction mixture was acidified with 1M HCl and concentrated in vacuo. The aqueous layer was diluted with ethyl acetate (75 ml) and water. The organics were washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was chromatographed (PTLC, SiO₂, 35% ethyl acetate/hexane) to give N-benzyloxy-1-{4-[5-cyano-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine-1-sulfonyl}-4-(N,N-dimethylaminosulfonyl)piperazine-2-(R)-carboxamide (71%) as a white solid.

Step 2

A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.54 ml, 1.54 mmol) was added to a solution of N-benzyloxy-1-{4-[5-cyano-1-(2-trimethylsilylethanesulfonyl)indole-3-yl]piperidine-1-sulfonyl}-4-(N,N-dimethylaminosulfonyl)piperazine-2-(R)-carboxamide (0.49 g, 0.62 mmol) and the reaction was placed in a 55° C. oil bath for 30 min. The reaction was diluted with 1 M HCl and concentrated in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with brine, dried over MgSO₄ and concentrated in vacuo to give N-benzyloxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]-4-(N,N-dimethylamino-sulfonyl)piperazine-2-(R)-carboxamide (99%) as a tan solid. This material was converted to N-hydroxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]-4-(N,N-dimethylamino-sulfonyl)piperazine-2-(R)-carboxamide by following Example 16, Step 5.

Proceeding as described in Example 20, Step 1 but substituting N-benzyloxy-1-{4-[5-cyano-1-(2-trimethylsilylethanesulfonyl)indole-3-yl]piperidine-1-sulfonyl}-1,4-piperazine-2-(R)-carboxamide with N-tert-butoxy-4-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}piperidine-4-carboxamide [prepared as described in Example 15 above] gave N-tert-butoxy-4-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-1-methanesulfonylpiperidine-4-carboxamide. This material was converted to N-hydroxy-4-{[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]amino}-1-methanesulfonylpiperidine-4-carboxamide by following Example 10, Step 2.

Example 21 Synthesis of N-hydroxy-1-{4-[5-(4-chlorophenyl)pyrrol-2-yl]piperidine-1-sulfonyl}piperidine-2-(R)-carboxamide ##STR32##

Step 1

A solution of 2-(4-chlorophenyl)pyrrole (409 mg, 2.3 mmol) in methylene chloride (15 ml) was added to a solution of trimethylsilyl trifluoromethanesulfonate (0.45 ml, 2.3 mmol) and methyl (R)-1-(4-piperidone-1-sulfonyl)piperidine-2-carboxylate (700 mg, 2.3 mmol) [prepared as described in Example 18, Step 1] in methylene chloride (20 ml) at 0° C. over a period of 15 min. Triethylsilane (0.71 ml, 9.2 mmol) was added and after stirring for 10 min., sat. sodium bicarbonate solution (35 ml) was added. The reaction mixture was extracted twice with methylene chloride and the combined organic extracts were washed with brine and dried over MgSO₄. The organic extracts were concentrated in vacuo and the residue was chromatographed (SiO₂, 25% ethyl acetate/hexane), to give methyl 1-{4-[5-(4-chlorophenyl)pyrrole-2-yl]piperidine-1-sulfonyl}piperidine-2-(R)-carboxylate (47%) as a white solid. This material was converted to N-hydroxy-1-{4-[5-(4-chlorophenyl)pyrrole-2-yl]piperidine-1-sulfonyl}piperidine-2-(R)-carboxamide (47%) by following Example 11, Step 1 and Example 17, Step 4.

Example 22 Synthesis of N-hydroxy-6-amino-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}hexanoamide ##STR33##

Step 1

Trimethylsilyl iodide (0.026 ml, 0.19 mmol) was added to a solution of N-hydroxy-6-(benzyloxycarbonyl)amino-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}hexanoamide (103 mg, 0.19 mmol) [prepared as described in Example 17, Step 3] in acetonitrile (2 ml) at 0° C. The reaction mixture was allowed to warm to RT, and additional trimethylsilyl iodide (0.47 mmol, 0.065 ml) was added in 0.5 equiv. portions over 2.5 h. Methanol (1.0 ml) was added and the reaction mixture was concentrated in vacuo. The residue was chromatographed (SiO₂, 2%-10% methanol/methylene chloride) to give N-hydroxy-6-amino-2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}hexanoamide (43.5%) as a tan solid.

Example 23 Synthesis of N-hydroxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]-4-cyclopropylmethylpiperazine-2-(R)-carboxamide ##STR34##

To a solution of N-benzyloxy-1-{4-[5-fluoro-1-(2-trimethylsilylethane-sulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(R)-carboxamide (424 mg, 0.68 mmol) [prepared by proceeding as described in Example 15, Steps 4 and 5, but substituting 4-(4,5,6,7-tetra-fluoroindol-3-yl)piperidinesulfamoyl chloride with 4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidinesulfamoyl chloride] in DMF (3 ml) was added potassium carbonate (470 mg, 3.4 mmol) and cyclopropylmethyl bromide (101 mg, 0.75 mmol) and the suspension was vigorously stirred at RT for 24 h. Water was added and the reaction was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO₄, and concentrated in vacuo. The residue was chromatographed (SiO₂, PTLC, 50% ethyl acetate/hexanes) to give N-benzyloxy-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine-1-sulfonyl}-4-cyclopropylmethylpiperazine-2-(R)-carboxamide e as a pale yellow oil. This material was converted to N-hydroxy-1-[4-(5-fluoroindol-3-yl)piperidine-1-sulfonyl]-4-cyclopropylmethylpiperazine-2-(R)-carboxamide by proceeding as described in Example 20, Step 2.

Example 24 Synthesis of N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-4-aminocarbonylpiperazine-2-(R)-carboxamide ##STR35##

Step 1

To a solution of N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide [prepared as described in Example 15, above] (600 mg, 1.23 mmol) in methylene chloride (8 ml) was added triethylamine (0.15 ml, 1.1 mmol) and tert-butyl-isocyanate (0.15 ml, 1.33 mmol). The reaction was stirred for 4 h, concentrated in vacuo, and the residue was chromatographed (SiO₂, PTLC, 50% ethyl acetate/hexanes) to give N-tert-butoxy-4-tert-butylaminocarbonyl-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (75%) as a clear oil.

Step 2

Trifluoroacetic acid (15 ml) was added to N-tert-butoxy-4-tert-butylaminocarbonyl-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (0.45 g, 0.92 mmol) [prepared as described in Step 2 above] and the reaction was stirred for 36 h. The reaction was concentrated in vacuo, and the residue was chromatographed (SiO₂, PTLC, 10% methanol/methylene chloride) to give N-hydroxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]-4-aminocarbonylpiperazine-2-(R)-carboxamide (55%) as a pale pink solid.

Example 25 Synthesis of N-hydroxy-2-(R)-{[4-(4-chlorophenylaminocarbonyl)piperazine-1-sulfonyl]amino}propionamide ##STR36##

Step 1

Hydrogen chloride gas was bubbled through a solution of methyl 2-(R)-[(4-tert-butoxycarbonylpiperazine-1-sulfonyl)amino]propionate (3.6 g, 10.7 mmol) [prepared by proceeding as described in Example 2, but substituting 4-(5-chloropyridin-2-yloxy)piperidine and D-valine methyl ester with 1-tert-butoxycarbonyl-1,4-piperazine and D-alanine methyl ester, respectively] in 10% dioxane/methylene chloride (100 ml) for 10 min. The reaction was stirred at RT for 4 h and concentrated in vacuo to give methyl 2-(R)-[(piperazine-1-sulfonyl)amino]propionate (91%) as a white solid that was used without further purification.

Step 2

To a solution of 4-chlorophenylisocyanate (0.33 g, 2.14 mmol) in diethyl ether (30 ml) was added methyl 2-(R)-[(piperazine-1-sulfonyl)amino]propionate (0.42 g, 1.8 mmol) [prepared as described in Step 1 above]. The reaction was stirred at RT for 2 h and filtered. The solid was washed with additional ether and the solid was collected to give methyl 2-(R)-{[4-(4-chlorophenylamino-carbonyl)piperazine-1-sulfonyl]amino}propionate (55%). This material was converted to N-hydroxy-2-(R)-{[4-(4-chlorophenylaminocarbonyl)piperazine-1-sulfonyl]amino}propionamide by following Example 13.

Proceeding as described in Example 25, Step 2 but substituting 4-chlorophenylisocyanate with 4-chlorobenzylisocyanate gave N-hydroxy-2-(R)-{[4-(4-chlorobenzylaminocarbonyl)piperazine-1-sulfonyl]amino}propionamide.

Example 26 Synthesis of N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-3-(phenylthio)propionamide ##STR37##

Step 1

Hydrogen chloride gas was bubbled through a solution N-tert-butoxy-2-(R)-tert-butoxycarbonylamino-3-(phenylthio)propionamide (3.45 g, 9.16 mmol) [prepared as described in Example 10, Step 1, by substituting 1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperidine-2-(R)-carboxylic acid with 2-(R)-tert-butoxycarbonylamino-3-(phenylthio)propionic acid] in methylene chloride at RT for 20 min. After 2 h, the reaction mixture was concentrated in vacuo to give N-tert-butoxy-2-(R)-amino-3-(phenylthio)propionamide HCl salt (79%) as a white solid that was used without further purification.

Step 2

To a solution of N-tert-butoxy-2-(R)-amino-3-(phenylthio)propionamide HCl salt (0.40 g, 1.31 mmol) and triethylamine (0.3 ml, 2.6 mmol) in tetrahydrofuran (25 ml) was added 4-(5-chloropyridin-2-yl)piperazinesulfamoyl chloride (0.39 g, 1.31 mmol). The reaction was stirred overnight at reflux and concentrated in vacuo. The residue was diluted with ethyl acetate (70 ml) and washed with water, brine, and dried over MgSO₄. The organics were concentrated in vacuo and the residue was chromatographed (SiO₂, 30% ethyl acetate/hexane) to give N-tert-butoxy-2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-3-(phenylthio)-propionamide (23%) as a white solid. This material was converted to N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl)piperazine-1-sulfonyl]amino}-3-(phenylthio)propionamide by following Example 24, Step 2.

Example 27 Synthesis of N-hydroxy-1-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]amino}cyclohexane-1-carboxamide ##STR38##

Step 1

To a suspension of methyl 1-aminocyclohexane-1-carboxylate HCl salt (4.06 g, 20.9 mmol) in acetonitrile (37 ml) was added sulfuryl chloride (26.2 ml, 326 mmol) and antimony pentachloride (0.17 ml, 2.4 mmol). The reaction was heated at 80° C. using a calcium sulfate drying tube overnight. The reaction was concentrated in vacuo to give methyl 1-(chlorosulfonylamino)cyclohexane-1-carboxylate (85%) as a yellow oil that was used without further purification. This material was converted to N-hydroxy-1-{[4-(4-chlorophenyl)-piperazine-1-sulfonyl]amino}cyclohexane-1-carboxamide by following Examples 2 and Example 13 except that the reaction was heated at 45° C.

Example 28 Synthesis of N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxamide ##STR39##

Step 1

Piperazine-2(R)-carboxylic acid dihydrochloride (5.0 g, 24.6 mmol) was suspended in hexamethyldisilazane (50 ml). The reaction mixture was heated at about 120° C. to achieve complete dissolution and then cooled to about 80° C. A solution of dimethylcarbamoyl chloride (3.18 g, 29.5 mmol) in acetonitrile (5 ml) was added and the reaction mixture is stirred overnight at about 80° C. A solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridinesulfamoyl chloride (5.4 g, 19.58 mmol) in acetonitrile (10 ml) was added and the resulting reaction mixture was stirred at about 80° C. till the completion of the reaction (followed by HPLC). The reaction mixture was cooled and then quenched with methanol. The resulting slurry was concentrated and then replaced into water. The aqueous slurry was made alkaline with ammonium hydroxide and then washed with dichloromethane. The aqueous phase was acidified with dilute HCl and extracted with dichoromethane. The organic extracts were washed with water and then evaporated to dryness to yield 4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridinesulfonyl]piperazine-2 (R)-carboxylic acid (6.1 g) as a beige colored solid.

Step 2

4-N,N-dimethylaminocarbonyl-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridinesulfonyl]piperazine-2 (R)-carboxylic acid (1.0 g, 2.27 mmol), [prepared as described in Step 1 above] was suspended in dichloromethane (8 ml) containing DMF (0.05 ml). The reaction mixture was cooled to -5° C. and oxalyl chloride (340 mg, 2.67 mmol) dissolved in dichloromethane (1 ml) was added. The reaction mixture was allowed to warm up slowly to about 15° C. and stirred for about 2 hours to achieve a clear solution. The reaction mixture was cooled to about -10° C. and a reagent mixture consisting of aqueous hydroxylamine (48%, 0.85 g, 12.35 mmol), THF (4.8 ml) and tert-butanol (1.9 g) was added slowly maintaining reaction temperature below 5° C. The reaction mixture was stirred at 5-15° C. for about 1 h and then replaced by vacuum distillation into acetonitrile (15 ml). Water (10 ml) was added to achieve a clear solution. Acetonitrile was slowly distilled off under reduced pressure to induce crystallization. After achieving a final volume of about 15 ml, distillation was discontinued and the resulting slurry was stirred at ambient temperature for 1 h. The precipitated product was isolated by filtration, washed successively with water, ethanol and isopropyl acetate and then dried under vacuum to yield N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxamide (850 mg) as a colorless crystalline solid.

1. Proceeding as described in Example 28, Step 4, but substituting 4-(4-fluoro-phenyl)-1,2,3,6-tetrahydropyridinesulfamoyl chloride with dimethylaminosulfamoyl chloride and using 3 equivalents of trimethylsilylcyanide gave 1-benzyloxycarbonyl-4-dimethylaminosulfonylpiperazine-2-(RS)-carboxylic acid. This material was converted to N-hydroxy-4-(N,N-dimethylaminosulfonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(RS)-carboxamide by proceeding as described in Example 28, Steps 3-5 above.

2. Proceeding as described in Example 28, Step 1 above, but substituting 1-benzyloxycarbonyl-4-tert-butoxycarbonylpiperazine-2-(R)-carboxylic acid with benzyl 1-benzyloxycarbonyl-4-tert-butoxycarbonylpiperazine-2-(RS)-carboxylate [prepared from 1-benzyloxycarbonyl-4-tert-butoxycarbonylpiperazine-2-(RS)-carboxylic acid as described in Ono, N., et al. Bull. Chem. Soc. Jpn., 51, 2401, (1978)] gave benzyl 1-benzyloxycarbonylpiperazine-2-(RS)-carboxylate. This material was first converted to benzyl 1-benzyloxycarbonyl-4-(2,2,2-trifluoroethyl)piperazine-2-(RS)-carboxylate by reacting it with 2,2,2-trifluoroethyl trichloromethanesulfonate as described in Gao, Y., et al. J. Med. Chem., 33, 39, (1990) and then to N-hydroxy-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]-4-(2,2,2-trifluoroethyl)piperazine-2-(RS)-carboxamide by following Example 28, Steps 3-5 described above.

Example 29 Synthesis of N-hydroxy-4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide ##STR40##

A mixture of 4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine-1-sulfonyl]piperazine-2-(R)-carboxylic acid (1.39 g, 3.16 mmol) [prepared as described in Example 28, Steps 1-4] and 10% Pd/C (0.7g) in 10% tetrahydrofuran/ethanol (45 ml) was stirred under an atmosphere of hydrogen (1 atm) overnight. The reaction mixture was filtered through Celite with excess ethanol and the filtrate was concentrated in vacuo to give 4-(N,N-dimethylaminocarbonyl)-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxylic acid (88%) as a white solid. This material was converted to N-hydroxy-4-dimethylaminocarbonyl-1-[4-(4-fluorophenyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide by following the procedure described in Example 28, Step 5 above.

Example 30 Formulation Examples

The following are representative pharmaceutical formulations containing a compound of formula I.

    ______________________________________                                         Tablet formulation                                                               The following ingredients are mixed intimately and pressed into single        scored tablets.                                                                                     Quantity per                                                                    Ingredient tablet, mg                                   ______________________________________                                           compound of this invention 400                                                 cornstarch 50                                                                  croscarmellose sodium 25                                                       lactose 120                                                                    magnesium stearate 5                                                         ______________________________________                                         Capsule formulation                                                              The following ingredients are mixed intimately and loaded into a              hard-shell gelatin capsule.                                                                         Quantity per                                                                    Ingredient capsule, mg                                  ______________________________________                                           compound of this invention 200                                                 lactose, spray-dried 148                                                       magnesium stearate 2                                                         ______________________________________                                         Suspension formulation                                                           The following ingredients are mixed to form a suspension for oral             administration.                                                                     Ingredient          Amount                                               ______________________________________                                           compound of this invention 1.0 g                                               fumaric acid 0.5 g                                                             sodium chloride 2.0 g                                                          methyl paraben 0.15 g                                                          propyl paraben 0.05 g                                                          granulated sugar 25.0 g                                                        sorbitol (70% solution) 13.00 g                                                Veegum K (Vanderbilt Co.) 1.0 g                                                flavoring 0.035 ml                                                             colorings 0.5 mg                                                               distilled water q.s. to 100 ml                                               ______________________________________                                         Injectable formulation                                                           The following ingredients are mixed to form an injectable formulation.           Ingredient             Amount                                              ______________________________________                                           compound of this invention 0.2 mg-20 mg                                        sodium acetate buffer solution, 0.4 M 2.0 ml                                   HCl (1N) or NaOH (1N) q.s. to suitable pH                                      water (distilled, sterile) q.s. to 20 ml                                     ______________________________________                                         Suppository formulation                                                          A suppository of total weight 2.5 g is prepared by mixing the compound       of                                                                               the invention with Witepsol ® H-15 (triglycerides of saturated           vegetable                                                                        fatty acid; Riches-Nelson, Inc., New York), and has the following             composition:                                                                         compound of the invention                                                                           500 mg                                               Witepsol ® H-15 balance                                                  ______________________________________                                    

Example 31 Isolation of Matrix Metalloproteases

The catalytic domain of human collagenase-1 was expressed as a fusion protein with ubiquitin in E. Coli as described in Gehring, E. R. et al., J. Biol. Chem., 270, 22507, (1995). After purification of the fusion protein, the collagenase-1 catalytic domain was released by treatment with 1 mM of aminophenylmercuric acetate (APMA) for 1 hour at 37° C. and then purified by zinc chelate chromatography.

Human collagenase-2 and gelatinase B were isolated in active form from buffy coats as described in Mookhtiar, K. A. et al., Biochemistry, 29, 10620, (1990).

The propeptide and catalytic domain portion of human collagenase-3 was expressed in E. Coli as an N-terminal fusion protein with ubiquitin. After purification, the catalytic domain was released by treatment with 1 mM APMA for 1 hour at 37° C., and then purified by zinc chelate chromatography.

Rat collagenase-3 was purified in active form from the culture media of uterine smooth muscle cells as described in Roswit, W. T. et al., Arch. Biochem. Biophys., 225, 285-295 (1983).

The catalytic and fibronectin-like portion of human progelatinase A was expressed as a fusion protein with ubiquitin in E. Coli. The assays were carried out on autolytically activated material.

The rat progelatinase A was purified from the culture media of interleukin-1 stimulated keratinocytes, activated by treatment with 1 mM APMA for 1 hour at 37° C., and subsequently dialyzed to remove excess APMA.

Human prostromelysin-1 was purified from the culture medium of synovial fibroblasts by affinity chromatography using an immobilized monoclonal antibody. The zymogen was activated by treatment with trypsin (1.5 μg/ml) for 1 hour at 23° C. to give a mixture of 45 and 28 kD species. The catalytic domain of human stromelysin-1 was prepared by expression and purification of prostromelysin-1 from E. Coli and activated with 1 mM APMA for 1 hour at 37° C., followed by dialysis.

Rat prostromelysin-1 was expressed in Chinese Hamster Ovary cells and purified from the culture media. It was activated by 1 mM APMA for 1 hour at 37° C., followed by dialysis.

Human promatrilysin was expressed and purified from Chinese Hamster Ovary cells as described in Barnett, J. et al., Prot. Expres. Pur., 5, 27, (1994). The zymogen was activated by treatment with 1 mM APMA for 1 hour at 37° C., and then purified by zinc chelate chromatography.

Example 32 Inhibition of Matrix Metalloproteases in Vitro

The matrix metalloprotease inhibitory activity of compounds of this invention in vitro was determined based on the hydrolysis of MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH₂ (Bachem, Inc.) at 37° C. as described in Knight, C. G., et al., FEBS Lett., 296, 263-266 (1992).

The matrix metalloprotease enzyme was diluted with assay buffer (50 mM Tricine pH 7.5, 200 mM NaCl, 10 mM CaCl₂, and 0.005% Brij-35) containing 10 μmole of above substrate dissolved in DMSO. Compounds of the invention dissolved in DMSO or only DMSO (control samples) were added such that the final DMSO concentration in all assays was 2.5%. The fluorescence changes were monitored with a Perkin-Elmer LS-50B flourimeter using an excitation wavelength of 328 nm and an emission wavelength of 393 nm.

Compounds of this invention were active in this assay.

The MMP inhibitory activities (expressed as IC₅₀, the inhibitor concentration causing 50% inhibition of the activity in the control) of some compounds of the invention were:

    ______________________________________                                         CPD         Collagenase-I                                                                             Collagenase-III                                           #  IC.sub.50, nm IC.sub.50, nm                                               ______________________________________                                         1           550        660                                                       16 22000 21                                                                    50 220 1.3                                                                     51 490 2.6                                                                     59 110 0.18                                                                    74 7600 0.73                                                                   102 338 0.92                                                                   105 129 0.59                                                                   106 223 0.52                                                                   133 20000 18                                                                   177 9300 1.6                                                                   179 23 0.073                                                                   242 67 0.063                                                                   254 >50000 181                                                                 255 120 0.19                                                                   256 26000 33                                                                   262 88 0.13                                                                    286 29 0.063                                                                   294 >50000 340                                                                 298 130 0.2                                                                    299 >50000 410                                                                 309 >50000 500                                                                 315 NA 0.1                                                                     342 170 2.1                                                                    345 530 6.6                                                                    355 650 56                                                                     401 250 0.19                                                                   413 9300 260                                                                   414 >50000 3400                                                                430 2200 890                                                                   431 >50000 6500                                                              ______________________________________                                    

Example 33 Degradation of Cartilage Plug in Vitro

The ability of the compounds of this invention to inhibit the degradation of the collagen matrix (as judged by release of hydroxyproline) was determined by the cartilage plug degradation assay in vitro by following a slight modification of the method described in Spirito, S., Doughty, E., et al., "Metalloproteinase inhibitors halt collagen breakdown in IL-1 induced bovine nasal cartilage cultures" Inflamm. Res., 44, Supp. 2: S131-S132, (1995).

Cartilage explants prepared from freshly sacrificed bovine knee joints were added to the culture medium (Dubelco's modified eagle medium, Gibco # 21063-001, Gibco BRL Products, Gaithersburg, Md.), without phenol red, but with HEPES, and L-glutamine and fungizone 2.5 μg/ml, gentamicin 50 μg/ml, penicillin 100 U/ml, and streptomycin 100 μg/ml). The cultures were stimulated with IL-1-α at a final concentration of 20 ng/ml. Compounds of Formula (I), were added at concentrations between 10 and 300 nm in DMSO. The control samples contained only IL-1-α. The cultures were incubated at 37° C. in an atmosphere of air with 6% CO₂ for 21 days during which time the medium was changed twice/week. The cartilage plugs were removed, hydrolyzed and the hydroxyproline content was determined. The MMP inhibitory activity of test materials is the measure of the hydroxyproline content in the test group relative to the vehicle treated group (control group).

The MMP inhibitory activities of some compounds of this invention in this assay were:

    ______________________________________                                         CPD #   % protection   CPD#    % protection                                    ______________________________________                                         50      71             60      89                                                51 35 100 68                                                                   59 54 242 27                                                                 ______________________________________                                    

Example 34 Cartilage Plug Degradation in Vivo

The activity of compounds of this invention in inhibiting the destruction of the collagen matrix was determined by the cartilage plug implant assay, in rats, using a minor modification of the method described in Bishop, J., et al., J. Pharm. Tox. Methods, 30, 19, (1993).

In this assay, bovine nasal cartilage plugs weighing approximately 20 mg were embedded in polyvinyl sponges impregnated with Mycobacterium tuberculosis and implanted subcutaneously in female Lewis rats. After a week, test materials, dissolved in DMSO (using a volume required for 5% final volume), were administered to female rats prepared as solutions or suspensions in an aqueous vehicle containing 0.9% sodium chloride, 0.5% sodium carboxymethyl-cellulose, 0.4% polysorbate 80, 0.9% benzyl alcohol (CMC vehicle). Control rats received vehicle alone. The experiment was terminated after 8 or 9 days. The plugs were removed, weighed, hydrolyzed, and the hydroxyproline content was measured. The MMP inhibitory activity of test materials is the measure of the hydroxyproline content in the test group relative to the vehicle treated group (control group).

The MMP inhibitory activities of some compounds of this invention in this assay were:

    ______________________________________                                         CPD #   % protection   CPD#    % protection                                    ______________________________________                                         50      70             74      46                                                51 45 100 40                                                                   59 58 179 63                                                                 ______________________________________                                    

Example 35 Inhibition of TNF Release in Vitro Assay

The activity of compounds of this invention in inhibiting the TNF release was determined, using the a minor modification of the method described in Pradines-Figueres, A. and Raetz, C. R. H., J. Biol. Chem., 267 (32), 23261, (1992).

Human Monomac 6 cells (Ziegler-Heitbrock, H. W. L., et al., Int. J. Cancer, 41, 456, (1988)) were cultured at 37° C. in RPMI 1640 medium containing 10% fetal calf serum to a density of 1×10⁵ cells/ml. 0.23 ml of these cells were placed in each well of a tissue culture plate and the cells were incubated for 15 min. The test compounds were dissolved in above mentioned medium and added and the incubation was continued for an additional 15 min. 10 μl of an lipopolysaccharide/phorbol-12-myristate -13-acetate (LPS/PMA) mixture was added such that the final concentration of lipopolysaccharide was 10 ng/ml and the final concentration of phorbol-12-myristate-13-acetate was 30 ng/ml. The cells were incubated for 2 h after which the plate was centrifuged and the medium was removed and analyzed for TNF content. The analysis was performed using a TNF Quantikine® Immunoassay (R & D Systems, Minneapolis, Minn. 55413) by following the manufacturer's protocol.

Compounds of this invention were active in this assay.

The TNF-α inhibitory activity of test materials, i.e., the measure of the TNF-α content in the test group relative to the vehicle treated group (control group) was:

    ______________________________________                                         CPD    Conc.    %        CPD    Conc.                                                                               %                                           #  μM inhibition # μM inhibition                                       ______________________________________                                         1      10       <15      298    2    70                                          16 10 <15 299 2 90                                                             50 10 <15 309 2 94                                                             74 10 17 313 2 73                                                              102 10 56 314 2 72                                                             105 10 20 315 2 86                                                             106 10 41 319 2 81                                                             133 10 32 321 2 93                                                             177 10 <15 355 10 <15                                                          179 10 <15 375 2 85                                                            242 10 85 381 2 10                                                             254 10 94 384 10 96                                                            255 10 97 401 10 97                                                            256 10 79 402 10 93                                                            262 2 90 409 10 86                                                             294 2 97                                                                     ______________________________________                                    

Example 36 Inhibition of LPS induced TNF-α Production in Mice in Vivo Assay

The activity of compounds of this invention in inhibiting the TNF-α release was determined, using a minor modification of the methods described in Zanetti, G.; Heumann, D., et. al., "Cytokine production after intravenous or peritoneal Gram-negative bacterial challenge in mice" J. Immunol., 148, 1890, (1992) and Sekut, L., Menius, J. A., et. al., "Evaluation if the significance of elevated levels of systemic and localized tumor necrosis factor in different animal models of inflammation" J. Lab. Clin. Med., 124, 813, (1994).

Female Balb/c mice were anesthetized and injected subcutaneously with the test compounds dissolved in CMC vehicle or hydroxypropylmethyl cellulose based vehicle. Control animals received only the vehicle. After 1 h, LPS (50 μg/mouse, Sigma #13129, Sigma Chemical Co., St. Louis, Mo.) was injected intraperitoneally. After 1.5 h, blood was collected from the retro-orbital plexus region of the animals in a microtainer serum separator tube (Becton Dickinson, Cat. No. #5960, Becton Dickinson & Co., Franklin Lakes, N.J.). The sera was separated and the amount of TNF-α was determined using the EM-TNFA® kit (Endogen, Woburn, Mass.) by following the manufacturer's protocol.

The TNF inhibitory activities of some compounds of the invention were:

    ______________________________________                                         CPD #   % inhibition   CPD #   % inhibition                                    ______________________________________                                         134     42             294     90                                                216 41 299 52                                                                  232 73 309 46                                                                  233 46 319 50                                                                  234 46 321 50                                                                  262 50                                                                       ______________________________________                                    

Example 37 TNF Receptor Shedding Immunoassay

Human Monomac 6 cells are cultured to a density of 1×10⁶ cells/mL at 37° C. in RPMI 1640 medium supplemented with 10% fetal calf serum. All subsequent incubations are performed at 37° C. 230 μl of these cells are placed in each well of a 96-well tissue culture plate and the cells are incubated for 15 minutes. 10 μl of desired concentration of compounds of formula (I) in the above mentioned medium are added to the appropriate wells and incubated for an additional 15 minutes. To each well is added 10 μl of PMA at a final concentration of 30 ng/mL. The cells are then incubated for 16 hours after which the plate is centrifuged and the medium is removed and analyzed for TNF receptor content. The analysis is performed using an R & D Systems TNF receptor Quantikine® Immunoassay (Endogen, Woburn, Mass.) following the manufacturer's protocol. Measurements of each TNF receptor (receptor I and receptor II) are performed in this way. The IC₅₀ is calculated from the percent inhibition of TNF released into the medium.

The compounds of Formula (I), when tested in this assay, exhibited the ability to selectively inhibit TNF production.

The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled.

All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted. 

What is claimed:
 1. A compound selected from the group of compounds represented by formula (I): ##STR41## wherein: R¹ and R² are independently selected from hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclo, heterocycloalkyl, heteroalkyl, or -(alkylene)-C(O)-X where X is alkyl, haloalkyl, alkoxy, haloalkyloxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, heteroaryloxy, hydroxy, aralkyloxy, heteroaralkyloxy, or heteroaryl; or R¹ and R² together with the carbon atom to which they are attached form a carbocycle or a heterocycle;R³ is hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocycloalkyl, heteroalkyl, (diphenylmethyl)alkyl, or -(alkylene)-C(O)-X where X is alkyl, haloalkyl, alkoxy, haloalkyloxy, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, aryloxy, heteroaryloxy, hydroxy, aralkyloxy, heteroaralkyloxy, or heteroaryl; or R³ together with either R¹ or R² and the atoms to which they are attached forms a heterocycloamino group; R¹⁰ is --NR¹¹ OR¹² wherein: R¹¹ and R¹² are independently selected from hydrogen, alkyl, or aralkyl; R²⁰ and R²¹ are independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaralkyl, or heteroaralkenyl; or R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a heterocycloamino group or an optionally substituted tetrahydropyridine or hexahydroazepine ring; or either of R²⁰ or R²¹ together with R³ forms an alkylene group; andtheir pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers, provided that R²⁰ and R²¹ together with the nitrogen atom to which they are attached do not form a morpholino ring either: (i) when R¹ and R³ are hydrogen and R² is aralkyl; or (ii) when R¹ and R³ together with the atoms to which they are attached form a tetrahydroisoquinoline ring and R² is hydrogen.
 2. The compound of claim 1 wherein R¹⁰ is --NHOH.
 3. The compound of claim 2 wherein R²⁰ and R²¹ together with the nitrogen atom to which they are attached form a heterocycloamino group.
 4. The compound of claim 3 wherein the heterocycloamino group formed by R²⁰ and R²¹ together with the nitrogen atom to which they are attached is a piperidino ring which is substituted with a substituent selected from aryl, heteroaryl, acyl, --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl), --OR (where R is aryl or heteroaryl), or --S(O)_(n) R (where n is an integer from 0 to 2 and R is aryl or heteroaryl).
 5. The compound of claim 4 wherein the substituent on the piperidino ring formed by R²⁰ and R²¹ together with the nitrogen atom to which they are attached is at the 4-position.
 6. The compound of claim 5 wherein R¹ and R² together with the atoms to which they are attached form a carbocycle or a heterocycle and R³ is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, or heteroalkyl.
 7. The compound of claim 6 wherein the heterocycle is a piperidino ring optionally N-substituted with an acyl, --SO₂ R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), or --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl) and R³ is hydrogen.
 8. The compound of claim 5 wherein:R¹ is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, or heteroalkyl; R² is hydrogen; and R³ is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, or heteroalkyl.
 9. The compound of claim 2 wherein:R³ and R¹ together with the atoms to which they are attached form a heterocycloamino group; R² is hydrogen; and R²¹ is aryl, aralkyl, or heteroaralkyl.
 10. The compound of claim 4 wherein R³ and R¹ together with the atoms to which they are attached form a heterocycloamino group and R² is hydrogen.
 11. The compound of claim 10 wherein the heterocycloamino group formed by R³ and R¹ together with the atoms to which they are attached is a piperidino ring.
 12. The compound of claim 1 wherein the substituent on the piperidino ring formed by R²⁰ and R²¹ together with the nitrogen atom to which they are attached is at the 4-position.
 13. The compound of claim 12 wherein the substituent on the piperidino ring formed by R²⁰ and R²¹ together with the nitrogen atom to which they are attached is phenyl, phenoxy, 4-(imidazol-1-yl)phenoxy, 5-chloropyridin-2-yloxy, 4-chlorophenoxy, 4-fluorophenoxy, 4-fluorophenyl, 4-chlorobenzoyl, 4-cyanobenzoyl, 4-methylbenzoyl, 4-chloro-phenylsulfonyl, phenylthio, pyridin-4-ylthio, pyridin-2-ylthio, benzoxazol-2-yl, benzothiazol-2-ylthio, 5-phenylthiazol-2-yl, 5-fluoroindol-3-yl, 6-chloroindol-3-yl, 5-phenylimidazol-2-yl, benzimidazol-2-yl, 4-methylphenylthio, 4-chlorophenylthio, 4-cyanophenyl, 4-fluorophenylaminocarbonyl, 4-fluorobenzoyl, 5-chloroindol-3-yl, 5-chlorobenzotriazol-1-yl, 6-methylindol-3-yl, 5-fluoroindol-3-ylcarbonyl, 6-fluoroindol-3-yl, 4,5,6,7-tetrafluoroindol-3-yl, 4-chloroindol-3-yl, 7-methylindol-3-yl, 5-cyano-indol-3-yl, 6-cyanoindol-3-yl, benzothiophen-2-yl, benzothiophen-3-yl, quinolin-3-yl, 5-chloro-benzimidazol-1-yl, pyridin-2-yloxy, 6-chloropyridin-2-yloxy, naphth-1-yl, naphth-2-yl, 7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, 8-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, 7-fluoro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, 8-fluoro-1,3-dihydro-2H-1,4-benzodiazepin-2-one-5-yl, or 1,2,3,6-tetrahydro-β-carboline.
 14. The compound of claim 10 wherein the heterocycloamino group formed by R³ and R¹ together with the atoms to which they are attached is a morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, or 2,2-dimethylthiomorpholino ring.
 15. The compound of claim 10 wherein the heterocycloamino group formed by R³ and R¹ together with the atoms to which they are attached is an optionally substituted piperazino ring.
 16. The compound of claim 15 wherein the substituent on the piperidino ring formed by R²⁰ and R²¹ together with the nitrogen atom to which they are attached is at the 4-position.
 17. The compound of claim 16 wherein the piperazino ring formed by R³ and R¹ together with the atoms to which they are attached is optionally substituted on the nitrogen at the 4-position with a substituent selected from alkyl, haloalkyl, cycloalkylalkyl, aralkyl, heteroaralyl, acyl, -(alkylene)-COOR^(a) (where R^(a) is alkyl), --SO₂ R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), --CONR'R" or -(alkylene)-CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl).
 18. The compound of claim 3 wherein the heterocycloamino group formed by R²⁰ and R²¹ together with the nitrogen atom to which they are attached is a piperazino ring which is substituted with a substituent selected from aryl, heteroaryl, --SO₂ aryl, or --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl).
 19. The compound of claim 18 wherein the substituent on the piperazino ring formed by R²⁰ and R²¹ together with the nitrogen atom to which they are attached is at the 4-position.
 20. The compound of claim 19 wherein R¹ and R² together with the atoms to which they are attached form a carbocycle or a heterocycle and R³ is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, or heteroalkyl.
 21. The compound of claim 20 wherein the heterocycle formed by R¹ and R² is a piperidino ring optionally N-substituted with an acyl, --SO₂ R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), or --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl).
 22. The compound of claim 19 wherein:R¹ is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, or heteroalkyl; R² is hydrogen; and R³ is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, or heteroalkyl.
 23. The compound of claim 22 wherein the substituent on the piperazino ring formed by R²⁰ and R²¹ together with the nitrogen atom to which they are attached is 4-chloro-phenyl, 4-cyanophenyl, 5-chloropyridin-2-yl, 5-nitropyridin-2-yl, 5-bromo-pyridin-2-yl, 4-benzyloxyphenyl, 4-(pyridin-4-ylmethyloxy)phenyl, pyridin-4-yl, 2-phenyl-benzoxazol-5-yl, 4-biphenylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, 4-benzyloxyphenylaminocarbonyl, 4-chlorophenylaminocarbonyl, or 5-trifluoromethylpyridin-2-yl and R³ is hydrogen.
 24. The compound of claim 19 wherein R³ and R¹ together with the atoms to which they are attached form a heterocycloamino group and R² is hydrogen.
 25. The compound of claim 24 wherein the heterocycloamino group formed by R³ and R¹ together with the atoms to which they are attached is a piperidino ring.
 26. The compound of claim 25 wherein the substituent on the piperazino ring formed by R²⁰ and R²¹ together with the nitrogen atom to which they are attached is 4-chlorophenyl, 4-cyanophenyl, 5-chloropyridin-2-yl, 5-nitropyridin-2-yl, 5-bromopyridin-2-yl, 4-benzyloxyphenyl, 4-(pyridin-4-ylmethyloxy)phenyl, pyridin-4-yl, 2-phenylbenzoxazol-5-yl, 4-biphenylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, 4-benzyloxyphenylaminocarbonyl, 4-chlorophenylaminocarbonyl, or 5-trifluoromethylpyridin-2-yl.
 27. The compound of claim 24 wherein the heterocycloamino group formed by R³ and R¹ together with the atoms to which they are attached is an optionally substituted piperazino ring.
 28. The compound of claim 27 wherein the piperazino ring formed by R³ and R¹ together with the atoms to which they are attached is optionally substituted on the nitrogen at the 4-position with a substituent selected from alkyl, haloalkyl, cycloalkylalkyl, aralkyl, heteroaralkyl, acyl, -(alkylene)-COOR^(a) (where R^(a) is alkyl), --SO₂ R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), --CONR'R" or -(alkylene)-CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl).
 29. The compound of claim 24 wherein the heterocycloamino group formed by R³ and R¹ together with the atoms to which they are attached is a morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, or 2,2-dimethylthiomorpholino ring.
 30. The compound of claim 2 wherein R²⁰ and R²¹ together with the nitrogen atom to which they are attached form an optionally substituted 1,2,3,6-tetrahydropyridine ring.
 31. The compound of claim 30 wherein the 1,2,3,6-tetrahydropyridine ring is substituted at the 4-position.
 32. The compound of claim 31 wherein:R¹ is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, or heteroalkyl; R² is hydrogen; and R³ is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, or heteroalkyl.
 33. The compound of claim 32 wherein the substituent on the 1,2,3,6-tetrahydropyridine ring is an aryl or heteroaryl ring.
 34. The compound of claim 31 wherein R¹ and R² together with the atoms to which they are attached form a carbocycle or a heterocycle and R³ is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl, or heteroalkyl.
 35. The compound of claim 34 wherein the heterocycle is a piperidino ring optionally N-substituted with an acyl, --SO₂ R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), or --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl) and R³ is hydrogen.
 36. The compound of claim 21 wherein R³ and R¹ together with the atoms to which they are attached form a heterocycloamino group and R² is hydrogen.
 37. The compound of claim 36 wherein the heterocycloamino group formed by R³ and R¹ together with the atoms to which they are attached is a morpholino, thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, or 2,2-dimethylthiomorpholino ring.
 38. The compound of claim 36 wherein the heterocycloamino group formed by R³ and R¹ together with the atoms to which they are attached is a piperidino ring.
 39. The compound of claim 38 wherein the substituent on the 1,2,3,6-tetrahydropyridine ring is an aryl or a heteroaryl ring.
 40. The compound of claim 36 wherein the heterocycloamino group formed by R³ and R¹ together with the atoms to which they are attached is an optionally substituted piperazino ring.
 41. The compound of claim 40 wherein the piperazino ring formed by R³ and R¹ together with the atoms to which they are attached is optionally substituted on the nitrogen at the 4-position with a substituent selected from alkyl, haloalkyl, acyl, -(alkylene)-COOR (where R is alkyl), --SO₂ R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), or --CONR'R" (where R' and R" are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl).
 42. The compound of claim 41 wherein the substituent on the on the 1,2,3,6-tetrahydropyridine ring is an aryl or heteroaryl ring.
 43. A process for preparing a compound of formula (I) selected from the compounds of claim 1, comprising the steps of:(i) (a) reacting a 2-[(aminosulfonyl)amino]acetic acid of formula: ##STR42## where Y is hydroxy, halo, alkyl or succinimido ester with a hydroxylamine of formula NR¹¹ OR¹², where R¹¹ and R¹² are as defined in claim 1, to provide a compound of formula (I); or (b) reacting a compound of formula: ##STR43## where R¹² is not hydrogen with a sulfamoyl chloride NR²⁰ OR²¹ SO₂ Cl, where R²⁰ and R²¹ are as defined in claim 1, to provide a compound of formula (I); (ii) optionally replacing R¹² with hydrogen, in a compound of formula (I) prepared in Step (i) above, where R¹² is not hydrogen to provide a corresponding compound of formula (I) where R₁₂ is hydrogen; (iii) optionally treating a compound of formula (I), prepared in Steps (i) or (ii) above, with an acid to provide a corresponding acid addition salt; (iv) optionally treating a compound of formula (I), prepared in Steps (i) or (ii) above, with a base to provide a corresponding free base; and (v) optionally separating a mixture of stereoisomers of a compound of formula (I) prepared in Steps (i), (ii), (iii), or (iv) above, to provide a single stereoisomer.
 44. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.
 45. A method of treatment of a disease in a mammal treatable by administration of a metalloprotease inhibitor, comprising administration to the mammal of a therapeutically effective amount of a compound of claim
 1. 46. The method of claim 45 wherein the disease is rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal disease, chronic pulmonary obstructive disease, aberrant angiogenesis, multiple sclerosis, restenosis, aneurysmal disease, tumor metastasis, or cornmeal ulceration. 